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Circulation Research “In This Issue” Anthology

Originally published9 Nov 2012https://doi.org/10.1161/RES.0b013e31826f7938Circulation Research. 2012;111:e294–e337

    Circulation Research, vol 106, 2010

    Regulation of cardiomyocyte polyploidy and multinucleation by Cyclin G1 (p 1498)1

    Liu et al have discovered a potent promoter of polyploidy in rat hearts.

    Polyploidy—multiple copies of the genome in one cell—is normal in cardio-myocytes but can also be ramped up in pathological situations, such as cardiac hypertrophy or in regenerative situations, such as after heart injury. The ability to boost or suppress polyploidy might thus have a number of heart health implications.

    Cardiomyocytes in the mammalian embryo divide just like regular cells, but shortly after birth, they stop dividing and continue replicating their DNA, creating cells with multiple nuclei. This multinucleation period lasts for about 3 weeks in rats and about 10 years in humans. Liu et al discovered that in the postnatal multinucleation phase in rats, levels of cyclin G1 protein shot up, whereas levels of other cell cycle regulators dropped. Cyclin G1, the team showed, boosted polyploidy in newborn rat cardiomyocytes, whereas the lack of cyclin G1 prevented polyploidy in newborn mice. Without cyclin G1, these mice were also less capable of increasing the number of their nuclei in response to cardiac overload and hypertrophy.

    Defective DNA Replication Impairs Mitochondrial Biogenesis In Human Failing Hearts (p 1541)2

    Failing human hearts have failing mitochondria in their cells. Kara-manlidis et al now show that defunct mitochondrial DNA (mtDNA) replication is to blame.

    The reduced replication, say the authors, was caused by a combination of low levels of replication fork factors and increased oxidative damage to the mtDNA. The problem lay not with replication initiation, but with DNA strand extension, consistent with the need to fix oxidative damage during the process. Preventing the oxidative damage might, therefore, provide a therapeutic avenue. A recent study showed that mitochondrial-targeted antioxidants could protect against both mtDNA depletion and left ventricular remodeling after myocardial infarction in mice. One of the most important aspects of the new report is that it usurps a previous theory for mitochondrial dysfunction in heart failure. Evidence from animal studies had suggested that low levels of the transcription coactivator PGC-1 cause reduced mitochondrial biogenesis. Although mitochondrial biogenesis was certainly reduced in the failing human hearts, mRNA levels of PGC-1 (a regulator of energy metabolism genes) were normal. Protein levels of PGC-1α were, in fact, increased. PGC-1 partner protein, ERRα (a known activator of many mitochondrial biogenesis genes) was significantly reduced, however. The authors, thus, flag ERRα as another possible target for therapy.

    Manipulation of Death Pathways in Desmin Related Cardiomyopathy (p 1524)3

    The good news is that antiapoptosis treatment extends life expectancy in a mouse model of desmin-related myopathy (DRM). The bad news is it only does so minutely, say Maloyan et al.

    DRM is a very rare but severe disease in which patients display progressive muscle atrophy and weakness, resulting in eventual death from heart, respiratory failure, or both. Disease progression is associated with the accumulation of aggregates of desmin and other proteins, and also with mitochondrial dysfunction and apoptosis. Although apoptosis can directly cause heart failure, it was not known to what extent apoptosis contributes to heart failure in DRM. Maloyan et al treated a cardiac-specific mouse model of DRM with an apoptosis blocker. Though this extended the life of the mice by a month or two, they still ultimately died of heart failure. Investigations revealed that in the absence of apoptosis, death still found a way, and instead, necrosis pathways were activated. The authors caution against therapies that target only one of the many cell death pathways. Those that target multiple pathways or failing mitochondria, from where many cell death pathways originate, might be a better bet.

    Amniotic Membrane-Derived Stem Cells (p 1613)4

    The best bet for fixing a broken heart might be amniotic stem cells, say Tsuji et al.

    Several types of stem cell have been investigated for their potential to differentiate into cardiac muscle and repair damaged hearts. Bone marrow-derived mesenchymal stem cells have been a recent favorite because they are naturally immunoprivileged (tolerated by the host’s immune system). Concerned that bone marrow cells might have low cardiac muscle differentiation efficiency, however, Tsuji et al looked for an alternative. Human amniotic membrane-derived mesen-chymal stem cells (AMCs), the team showed, differentiate into cardiac muscle with high efficiency both in vitro and in vivo. These cells also improved rat heart function following myocardial infarction. Because amniotic material is tolerated by the mother’s immune system during pregnancy, the team reasoned, AMCs should show strong immunoprivilege. And they did: AMCs were still present in the rat hearts 80 days after transfer. Immunoprivilege in the AMCs came down to their secretion of a molecule called HLA-G. Treating AMCs with cytokine IL-10 boosted HLA-G secretion and thus the cells’ tolerability. As a surprising added bonus, however, IL-10 treatment also improved the AMC’s differentiation efficiency.

    IL-17A Is Essential for Dilated Cardiomyopathy (p 1646)5

    Inhibiting cytokine IL-17A might save inflamed hearts from failure, report Baldeviano et al.

    Inflammation of the heart (myocarditis) is caused by infection and/or autoimmunity and can often lead to heart muscle deterioration and death. Indeed, myocarditis-induced dilated cardiomyopathy (DCM) is a major cause of sudden death in young adults. Baldeviano et al show that in a mouse model of autoimmune myocarditis, IL-17A-secreting cells (Th 17 cells) turn up at the battleground, suggesting that IL-17A might be a molecular provocateur of pathology. To the team’s surprise, autoimmune myocarditis raged on in mice that genetically lacked IL-17A as well as in mice where IL-17A activity was blocked with neutralizing antibodies. However, there was one important difference. In mice lacking IL-17A, autoimmune myocarditis never led to the potentially fatal DCM. This is likely to be because enzymes that regulate heart remodeling and fibrosis (processes involved in DCM) were diminished. Patients with DCM have also been reported to have high levels of IL-17A in their blood, suggesting that a similar mechanism is at work in humans and that a similar therapeutic strategy, if given early enough, might save lives.

    HO1 and DC Function in Transplant Arteriosclerosis (p 1656)6

    Cheng et al have uncovered how an enzyme that promotes cell survival can also help protect transplanted blood vessels from rejection.

    Transplanted tissues and organs are susceptible to attack from the host’s immune system. The instigators of the attack are dendritic cells, which display antigens from the grafted tissues (in combination with MHC class II molecules) to host lymphocytes, inciting them to strike. In the blood vessels of transplanted tissue, the continuous immune attack leads to progressive arteriosclerosis (blood vessel scarring). This is a common cause of failure in heart transplantation. In rats, it was reported that tissue graft survival could be prolonged if heme oxygenase 1 (HO-1) levels were increased. HO-1 is known to be cell protective and has antioxidant, anti-apoptotic, and immune-modulatory activities. How exactly this enzyme might protect grafts from rejection, however, was unclear. Cheng et al have now shown in mice that if host dendritic cells lack HO-1, they mount a far more pronounced immune attack against blood vessel grafts. Investigations revealed that HO-1 normally suppresses key factors in the MHC class II antigen presentation pathway.

    CCR1 Enhances MSC Survival, Migration, Engraftment (p 1753)7

    Give stem cells more CCR1, and give cell replacement therapy a better chance, say Huang et al.

    CCR1 is the cell surface receptor for chemokine CCL7, which along with other chemokines, gets ramped up in the heart after myocardial infarction. Chemokines are a known trigger for cell migration, suggesting they might be important in the heart’s healing process. Adult mesenchymal stem cells (MSCs), which are a favorite candidate for cell replacement therapies, have very low levels of CCR1. Huang et al wondered whether this might be the reason that MSCs, when transferred into damaged hearts, neither engraft very well nor survive in big numbers. The team genetically engineered mouse MSCs to express more CCR1. These engineered cells migrated more efficiently and resisted cell death in vitro and, more importantly, engrafted and survived in high numbers in infarcted mouse hearts. The cells also reduced the infarction size, increased capillary density, restored heart function, and prevented adverse heart remodeling. Finding a way to raise CCR1 levels in MSCs may be a new strategy for improving the outcome of heart cell replacement therapies.

    CHIP Protects the Heart by Degrading p53 (p 1692)8

    If the heart attack does not kill you, the subsequent tissue damage might. Now, Naito et al have found a way to reduce that tissue damage.

    The destruction of ischemic heart tissue after a heart attack can lead to adverse remodeling and heart failure. Destruction occurs largely by cellular suicide (apoptosis), and the pro-apo-ptosis factor p53 is thought to be involved in this process. The levels of p53 rise in the heart after an attack, and deletion of p53 has been shown to improve postattack heart function. Naito and colleagues looked for an endogenous factor that antagonizes p53 function, in the hope that they might ultimately co-op its mechanism to treat heart attack victims. After screening a heart-specific expression library, they found a protein called CHIP. CHIP reduced p53 levels by tagging it for destruction. Following hypoxia, however, CHIP levels dropped, allowing p53 to accumulate. By overexpressing CHIP in mouse hearts, the team showed that preventing p53 accumulation and apoptosis of heart cells decreased adverse heart remodeling. The drug 17-AAG, which degrades CHIP targets, also reduced p53 levels. The authors caution, however, that 17-AAG has a nonspecific effect, and they recommend instead a more specific CHIP/ p53-targeted therapy.

    FKBP12.6-RyR2 Binding in Myocytes (p 1743)9

    Guo et al describe the molecular dynamics of some key players in heart muscle excitation-contraction coupling.

    In muscle cells, excitation-contraction coupling is the process whereby action potential across the cell membrane prompts the release of calcium into the cytoplasm and subsequent activation of calcium-sensitive contractile proteins. Calcium release is controlled by ryanodine receptors—channel proteins in the membrane of the sarcoplasmic reticulum (the calcium store). Dysfunctional ryanodine receptors are thought to cause arrhythmias and heart failure. Guo et al have looked at the dynamics of two proteins, FKBP12.6 and FKBP12, which are known to bind ryanodine receptors, but whose exact function remains elusive. The team found that practically all of the FKB12.6 in heart muscle cells bind to ryanodine receptors. It binds tightly, much more so than FKBP12, and can directly affect the receptor’s function— reducing the release of calcium. FKBP12 has no such effect. Intriguingly, however, whereas FKBP12 is abundant in the cell, FKBP12.6 is scarce—practically all of it is used up, binding to just 10% to 20% of the receptors. FKBP12.6 is thus unlikely to be critical for guarding against ryano-dine receptor disfunction and arrythmia.

    FXR in Vascular Calcification (p 1807)10

    It might seem unlikely, but boosting the activity of a bile acid receptor prevents vascular calcification, report Miyazaki-Anzai et al.

    Besides being highly expressed in liver, kidney, and intestine where bile acids are abundant, the bile acid receptor FXR has also been reported to be expressed in vascular smooth muscle and endothelial cells and has been found in atherosclerotic lesions. What it is doing in blood vessel walls, however, was a mystery. Miyazaki-Anzai and colleagues discovered that FXR was highly induced in both a cellular and mouse model of aortic calcification. Boosting FXR activity using the FXR agonist drug INT-747 inhibited calcification in vascular cells, whereas blocking FXR did the opposite. Importantly, oral delivery of INT-747 prevented vascular calcification in a mouse model of chronic kidney disease. Clinical studies have shown that more than half of patients with chronic kidney disease die of cardiovascular complications, with one common cause being calcific arterial disease. Thus, perhaps INT-747 (currently in clinical trials for diabetes and primary biliary cirrhosis) could also be used to reduce the risk of death in chronic kidney disease patients.

    Proepicardial Organ Specification in Zebrafish (p 1818)11

    Liu et al have identified two factors that prompt the formation of cells that form other cells that form the heart.

    The factors BMP4 and Tbx5a, the team say, prompt formation of the zebrafish proepicardium (PE)—a cluster of cells that develops into the epicardium, which in turn gives rise to essential cell types and structures of the heart. BMP signaling had been previously implicated in PE development from studies in chick embryos, but which particular BMP member might be responsible was unknown. The team looked at the timing of expression of different BMPs in zebrafish embryos, and BMP4 fitted the bill. Furthermore, BMP4 mutants lacked expression of PE developmental markers. By contrast, Tbx5 had been reported in chick embryos to be important for migration of PE cells. The team was thus surprised to find that in zebrafish, Tbx5 was essential early in PE development, earlier than BMP signals, in fact. Knock out of Tbx5 did not affect BMP4 expression, however, suggesting that the two act independently. Because epicardium activation in the adult zebrafish is essential for heart regeneration, the newly identified factors might suggest a means to regenerate injured human hearts, too.

    ABCA1, ABCG1, and Efferocyte Apoptosis (p 1861)12

    Yvan-Charvet et al have discovered how two cholesterol-clearing proteins protect macrophages from apoptotic cell death.

    In atherosclerotic vessels, clearing away dead cells keeps the lesions from quickly getting worse. The dead cell trash collectors are the macro-phages, but theirs is a risky business, for the very act of cleaning up endangers their lives. Or so it would were it not for the cholesterol transporter proteins ABCA1 and ABCG1. It has been shown that mice that lack these transporters have an excessive accumulation of dead macrophages throughout their tissues and atherosclerotic lesions. Yvan-Charvet et al have now shown that when macro-phages lacking the transporters gobbled up cellular corpses, the ingested membrane lipids and cholesterols triggered the assembly of NADPH oxidase complexes. This resulted in an excessive intracellular burst of damaging reactive oxygen species, which in turn prompted the activation of apoptotic pathways. The transporter proteins, which are normally upregulated in macrophages after ap-optotic cell ingestion, appear to keep a cap on reactive oxygen species production—no doubt by ridding the macrophage of its enormous lipid load.

    Circulation Research, vol 107, 2010

    EHD-Targeting Proteins in Heart (p 84)13

    Gudmundsson et al have identified four new members of the membrane maintenance team of heart cells.

    The excitability of heart cells depends on the tight regulation of their plasma membrane-associated proteins, such as ion channels, transporters, and receptors. Although much is known about the function of these frontline players, much less is understood about how they get to and from the membrane. Gudmundsson et al looked for members of the behind-the-scenes protein trafficking troops. They knew ankyrin B was such a protein and that it was present in heart cells, so they looked for ankyrin B interaction partners. They found EHD3—a protein known to be involved in trafficking in other cell types. One of ankyrin B’s cargoes is the conduction-controlling Na+/ Ca2+ exchanger. The team found that EHD3 enhanced membrane delivery of the exchanger and accordingly increased the heart cells’ conduction. EHD3 has a number of close relatives—EHD1, 2, and 4—and these also bound ankyrin B in heart cells. All four proteins were upregulated in the absence of ankyrin B, and the authors suggest this may reflect some form of compensatory mechanism aimed at maintaining the delivery of membrane proteins.

    (P)RR/ATP6AP2 Is Essential for V-ATPase Assembly (p 30)14

    The blood pressure regulator, (pro)renin receptor, has a secret double life that Kinouchi et al have now uncovered.

    When blood pressure drops, the kidneys secrete the hormone renin. This sets up a chain of events that leads to blood vessel constriction and water and sodium reabsorption into the blood, both of which increase blood pressure. The (pro)renin receptor is a crucial activator of this pathway, and its function has been well studied. It was reported recently, however, that a truncated version of the receptor associates with V-ATPase—a membrane-associated proton pump that controls acidification of intracellular vacuoles, such as lysosomes and endosomes. The relationship between (pro)renin receptor and V-ATPase in vivo was unknown, so Kinouchi et al set out to investigate just that. They showed that mice that specifically lacked (pro)renin receptor in their hearts suffered heart failure after only a few weeks of life. The cells of the mutant hearts had large vesicles containing partially or completely undigested cell components, suggesting acidification of these vesicles was impaired. Indeed, further studies in cell culture suggested that (pro)renin receptor was needed for assembling the V-ATPase subunits into a functional pump.

    Therapeutic Targeting of Mitochondrial Superoxide (p 106)15

    Dikalova et al unveil a potential new treatment for high blood pressure—a mitochondrial-targeted antioxidant.

    Reactive oxygen species (ROS) are known perpetrators of pathology in hypertension and many other human diseases, yet clinical trials with antioxidants have proven largely ineffective. An important natural cellular antioxidant is superoxide dismutase, and mammals have three versions of this enzyme— one extracellular, one cytoplasmic, and one mitochondrial. Mice that lack just one copy of their mitochondrial superoxide dismutase (SOD2) are prone to hypertension. Furthermore, the hypertension-inducing hormone, angiotensin II, increases mitochondrial ROS. Dikalova et al, therefore, reckoned that targeting an antioxidant drug directly to the mitochon-drial ROS production site might halt hypertension. mitoTEMPO is one such drug. The team showed that mitoTEMPO reduced mitochondrial production, and cellular levels, of ROS in cultured aortic endothelial cells. The drug also reduced blood pressure and improved vascular relaxation in mice that had been given angiotensin II or a high-salt diet. Importantly, mitoTEMPO did not lower blood pressure in normal mice—an undesirable effect of many existing hypertension treatments.

    Vascular Inflammation, T cells, and Hypertension (p 263)16

    T cells do not instigate hypertension but they make it a whole lot worse, Marvar et al suggest.

    The team had previously found in mice that T cells are essential mediators of angiotensin II-induced hypertension. Their next question was: How does angiotensin II activate the T cells? Angiotensin II is known to work on the brain, and it has been shown that lesions in the anteroventral third cerebral ventricle prevent angiotensin’s hypertensive action. The team found that such lesions also prevented angiotensin-induced T-cell activation. However, the brain lesions did not prevent hypertension and T-cell activation in mice treated with norepinephrine, which works directly on the blood vessels. Together, these results suggest that angiotensin’s effect on T cells might be the result of the hypertension itself. The team gave hydralazine—a smooth muscle relaxant and antihypertensive agent—to normal mice treated with angiotensin. Sure enough, T-cell activation was inhibited. Given that T cells not only promote hypertension but also, as shown here, are activated by hypertension, the team suggests a feed forward mechanism whereby T cells add fuel to the growing blood pressure fire.

    MRTF-A Promotes Cardiac Fibrosis (p 294)17

    Small et al suggest a strategy to stop hearts from scarring and, thus, to save lives.

    Ironically, the healing process after a heart attack is itself a danger to the health of the heart. The scarring (fibrosis) can lead to reduced contractility, reduced vascularization, arrhythmias, and ultimately heart failure. Understanding the process of fibrosis is the first step toward suppressing its dangerous effects. Parts of the process are known. For example, it is thought that myofibroblasts are key regulators of fibrosis and that a protein kinase called ROCK is required for myofibroblast activation. Small et al looked downstream of ROCK to see if they could identify additional components of the fibrosis pathway. MRTF-A is a mediator of ROCK signaling, and the team showed that MRTF-A prompted a myofibroblast phenotype in cultured heart fibro-blasts, including the production and secretion of collagen, the major component of the extracellular matrix. More importantly, they also showed that mice that lacked MRTF-A were protected from fibrosis after suffering a heart attack. MRTF-A could thus be a promising target for therapy.

    Cardiomyocyte Renewal in Humans (p 305)18

    Kajstura et al reveal the rates of heart cell regeneration.

    Until a few years ago, the prevailing view of heart cells was that they were postmitotic and irreplaceable. The discovery of cardiac stem cells challenged that presumption. However, it remains unclear exactly which cells were regenerated, how often, and to what extent. Kajstura et al came up with the original idea of looking at the hearts of cancer patients that had been treated with iododeoxyuridine (IdU). This thymidine analog is given as part of radiotherapy; it incorporates into DNA during replication, making cycling cells (such as cancer cells) sensitive to radiation damage. Other cycling cells pick up IdU, too, and pass it on to their progeny. The team thus looked to see how many and what type of IdU-positive cells were present in the hearts of patients who died. They found IdU-labeled cardiomyocytes, endothelial cells, and fibroblasts. By counting the number of cells and dividing it by the time between IdU treatment and death, they calculated that cardiomyocytes regenerated at a rate of approximately 22% per year, fibroblasts at 20%, and endothelial cells at 13%. These rates are much higher than previously estimated and are sufficient, says the team, for the entire heart to be replaced several times over a lifetime.

    Cardiac Reporter iPS Cell Lines (p 340)19

    Good news: induced pluripotent stem (iPS) cells and embryonic stem (ES) cells make virtually identical cardiac progenitor cells, report van Laake et al.

    Reproducible results are everything in science, which is why it is so important to limit one’s experimental variables. Reports of variance between ES and IPS cell lines have, thus, raised concerns regarding the ability to compare results from one line with the next. What was not known, however, was whether the heterogeneity seen in undifferentiated ES and IPS lines persists as the cells differentiate into specific cell types. To address this issue, van Laake and colleagues compared ES and IPS cell lines from mice that contained a cardiac-specific fluorescent reporter transgene. The reporter allowed for the detection and sorting of cells that had differentiated to become cardiac progenitors. Microarray comparison of ES- and IPS-derived fluorescent cardiac progenitors revealed that from 28,853 transcripts, only 195 were significantly different—less than 0.7%. The team also found that variation between individual IPS cell lines was far less than expected.

    Hypoxia and PKCε Gene Repression (p 365)20

    Patterson et al reveal how lack of oxygen to the fetus represses a cardioprotective gene for life.

    It is known that stress to the developing fetus can lead to increased risk of ischemic heart disease later in life. One major cause of intrauterine stress is hypoxia, which can be caused by, among other things, anemia, placental insufficiency, and preeclampsia. It has been shown that hypoxic treatment of pregnant rats causes vulnerability to cardiac ischemia in male offspring. It has also been shown that such male offspring have lower levels of a cardioprotective protein (PKCε) in their hearts. Patterson et al now show that low PKCε in fetuses and offspring is due to methylation of transcription factor binding sites in the PKCε gene’s promoter region. Interestingly, this methylation and the resulting downregulation of PKCε expression are more pronounced in males than females. It is not clear why there is this sex-dependent difference, although the team did observe that in the hearts of female fetuses, the PKCε transcription factor binding sites associated with estrogen receptors. The team suggests that this association somehow protects against methylation of the chromatin.

    Dilated Myopathy in Newborns (p 429)21

    Cardiac stem cells are busy after birth, say Urbanek et al. The team’s findings refute previous suggestions that myogenesis is minimal after embryogenesis.

    Immediately after birth, the mammalian heart undergoes a rapid increase in size to accommodate the increased demand of the circulatory system. It was thought that this growth was almost entirely due to hypertrophy of existing cardiomyocytes—a process of cellular expansion without division. This group of researchers recently identified the existence of cardiac stem cells (CSCs) in the hearts of adult mice. They thought it likely that such cells were also present in the newborn heart and wondered whether CSCs might contribute to the rapid neonatal heart growth. CSCs were indeed present, and the majority expressed the receptor for Notch1—a transmembrane protein that regulates cell fate decisions in various developmental settings. Overexpression of Notch1 pushed the CSCs into a proliferative state, whereas blocking Notch1 prevented myogenesis. Without Notch1, newborn hearts did not grow as they should and mice suffered dilated cardiomyopathy and increased mortality. Cardiomyogenesis, thus, not only occurs in the newborn, but also is absolutely essential.

    PHLPP-1 Negatively Regulates Akt in the Heart (p 476)22

    Inhibiting PHLPP-1 might keep injured heart cells alive after a heart attack, say Miyamoto et al.

    The death of heart cells after ischemia and reperfusion leads to scarring and reduced contractile function. Minimizing the extent of such cell death is, thus, a prime objective for cardiologists. A protein kinase and antiapoptosis factor called Akt is well known for its cardioprotective ability. Thus, figuring out how to boost Akt activity in injured heart tissue might help cardiologists in preserving viable myocardium and preventing scarring. Switching off Akt inhibitors might be one approach. A number of protein phosphatases are known to inhibit Akt but they are not specific to Akt, raising concern that unrelated proteins and pathways might also be affected. Recently, a protein phos-phatase called PHLPP-1, which selectively dephosphorylates Akt, has been identified. Whether PHLPP-1 exists or works in heart cells, however, is unknown. Miyamoto et al have now reported that PHLLP-1 was, indeed, expressed in mouse heart cells and that genetically deleting PHLLP-1 increased Akt activation in both heart cells and the ex vivo mouse heart. Since Akt is an antiapoptotic factor, boosting its activity in the long term might pose a cancer risk. The next step for researchers, therefore, is to figure out how PHLLP-1 might be inhibited both transiently and locally at the site of ischemic injury.

    Arrhythmogenic Purkinje Cells (p 512)23

    Long-suspected to be behind ventricular arrhythmias, Purkinje cells have finally been nailed as the culprits, thanks to Kang et al.

    The first suggestion that Pur-kinje cells of the cardiac conduction system might be involved in cardiac arrhythmias came 40 years ago. Although many studies have provided data that support this hypothesis, formal proof has been lacking. To address the issue, Kang et al observed the behavior of Purkinje cells and ventricular myocytes—another possible culprit—to see which of the two was more electrically erratic. Spontaneous calcium sparks—unprovoked releases of calcium from intracellular stores— were significantly more common in Purkinje cells, the team showed. Purkinje cells from a mouse model of catecholaminergic polymorphic ventricular tachycardia (CPVT)—a life-threatening arrhythmia—were particularly erratic, with up to 62% of cells showing spontaneous sparks. This figure rose to 90% of cells upon catecholaminergic stimulation. Such stimulation is a trigger for tachycardia in CPVT sufferers. The authors suggest that antiarrhythmia drugs, focused to target Purkinje cells, may be beneficial for CPVT and other arrhythmia disorders.

    Elastin and Aortic Valve Disease (p 549)24

    Elastin-lacking mice are excellent models for latent aortic valve disease, claim Hinton et al.

    Aortic valve disease, including aortic stenosis (insufficient valve opening) and aortic regurgitation (backward blood flow), is a common cardiac condition, with approximately 100,000 valve replacements being performed in the United States each year. Little is known about the pathology, although abnormalities in extracellular matrix (ECM) proteins are often associated with the disease. Hinton et al focused on one of the major ECM proteins—elastin. Mice with only one functional elastin allele, and thus expressing only half of the normal level of the protein, developed progressive aortic valve disease, showed the team. Valve structural abnormalities, such as thinning of the cusps, got progressively worse, as did aortic stiffening. The team also looked at genes, pathways, and cells affected by the absence of elastin. Among other things, they found aberrant activation and proliferation of valve interstitial cells and maladaptive ECM remodeling. Malformations were particularly apparent in the annulus— the ring of connective tissue that anchors the valve to the artery wall—pointing to this structure for future clinical focus.

    Mitochondrial Regulation of Arterial Contractility (p 631)25

    Narayanan et al uncover the cause and effect of rising mitochondrial calcium levels in arterial muscle cells.

    Muscle cell contractility is regulated by, among other things, changes in intracellular calcium. The sarcoplasmic reticulum (SR) is the major intracellular calcium store, but mitochondria can also take up and sequester calcium. What prompts the mitochondria to take up calcium and what effect the increase in mitochondrial calcium might have were two unknowns. Narayanan et al have now shown in rat arterial smooth muscle cells that mitochondrial calcium uptake is increased in response to SR calcium release (induced by endothelin treatment). Interestingly, mitochondrial calcium uptake did not occur in response to global intracellular calcium increase (induced by plasma membrane depolarization). Mitochondria can reside next to SR in cells, suggesting that a localized calcium boost might be needed to trigger mitochondrial uptake. The endothelin-induced increase in mi-tochondrial calcium resulted in the release of mitochondrial reactive oxygen species, which activated expression of a calcium channel protein, Cav1.2. The activation of Cav1.2, in turn, triggered vasoconstriction. Altered levels of reactive oxygen species, Cav1.2, and vascular contractility have all been associated with hypertension. Thus, the new work suggests that mitochondrial calcium control may be a useful target for hypertension drug development.

    IP3R Signaling Regulates Cardiac Hypertrophy (p 659)26

    Blocking IP3 receptor signaling could reduce hypertrophy, according to Nakayama et al.

    An increase in the size of heart cells—hypertrophy—can occur for physiologic and pathologic reasons. Pathologic hypertrophy, if left unchecked, could lead to heart failure and death. A number of prohypertrophic stimuli have been shown to increase intracellular levels of inositol 1,4,5-triphosphate (IP3) but the importance of IP3 in transducing the hypertrophic response has not been thoroughly established. Nakayama et al have made transgenic mice that overexpress an IP3 receptor and also mice that express an IP3 chelator, which mops up IP3, thus inhibiting IP3 signaling. Mice overexpressing the receptor developed mild hypertrophy by 3 months of age and were susceptible to more serious disease in response to hypertrophic stimuli. In line with these results, mice expressing the IP3 chelator showed reduced symptoms in response to hypertophic agents. The IP3 receptor resides on the sarcoplasmic reticulum (SR), and when it binds IP3, it activates the release of calcium from the SR. Mice that overexpressed IP3 receptor were protected against induced hypertrophy if they lacked calcineurin—a calcium-dependent phosphatase. Thus, blocking the IP3-to-calcineurin pathway could be one approach to reducing hypertrophy.

    Circulating MicroRNAs in Coronary Artery Disease (p 677)27

    Preliminary studies by Fichtlscherer et al suggest potential new biomarkers for coronary artery disease— circulating microRNAs.

    MicroRNAs (miRs) are short RNA molecules approximately 20–25 nucleotides in length that bind to and down-regulate target messenger RNAs. Although miRs generally act within the cell, recent reports have shown that miRs can be released into the blood stream. The circulating levels of certain miRs have been found to be altered in humans and animal models after a heart attack, and in patients with heart failure, a particular circulating miR has been identified as a potential prognostic biomarker. Fichtlscherer et al decided to look at the profile of circulating miRs in patients with coronary artery disease, the number one cause of death worldwide. They found that the endothelial cell miRs, miR-126, 17 and 92a, as well as the smooth muscle enriched miR-145, were reduced in patient plasma. Levels of the inflammation-associated miR-155 were also reduced. In contrast, two cardiac muscle miRs were increased. The finding that the endothelial cell miRs were reduced surprised the team, because vessel wall injury might be expected to increase release of these miRs; however, the mechanism for release or uptake of these miRs is, so far, entirely unknown.

    Nrg1 Sustains the Cardiac Gene Regulatory Network (p 715)28

    Lai et al report that Neuregulin 1, an essential heart development factor, regulates a network of genes in the developing ventricles.

    Neuregulin (Nrg)1— ligand of a transmembrane receptor called ErbB—is expressed in the heart’s endocardium and is crucial for ventricular morphogenesis during development. Without Nrg1, trabeculation—the formation of structural ridges on the ventricle walls that set up correct electrical conduction—is impaired. Downstream signals of Nrg1 have been identified, but how Nrg1 ultimately affects the cardiac gene regulatory network was unknown. The team created mutant mice that lacked almost, but not all, Nrg1 and looked at the expression of 15 different cardiac genes during heart development. They found that a majority of these genes showed decreased expression and that, although Nrg1 is known for its involvement in trabeculae formation, genes in both trabecular and nontrabecular tissue were affected. Also, across the ventricular walls of the mutant mouse hearts, the gene expression levels were graded, suggesting differential activity of Nrg1. Recent evidence suggests that ventricle growth and trabeculae formation are influenced by hemodynamic forces. The authors suggest that such forces might stimulate Nrg1 expression—hence, the graded expression pattern—and that because Nrg1 promotes heart development, its stimulation by blood flow would set up a positive feedback loop of function and form. Aberrations to this loop, say the authors, might magnify congenital malformations in the developing heart.

    AKAP5 Signaling Complexes in Heart (p 747)29

    The protein AKAP5 is crucial for controlling the heart’s fight-or-flight response, say Nichols et al.

    A-kinase anchoring proteins (AKAPs) help to spatially organize signaling events inside cells by targeting cAMP-dependent protein kinase A (PKA) to specific locations and complexes. More than 11 AKAPs have been identified in heart cells, and figuring out each of their individual roles remains a major long-term goal. For now, Nichols et al have focused their attention on AKAP5. The team made transgenic mice that lack AKAP5 and looked at the ability of the heart muscle cells to respond to sympathetic stimulation—a process that produces large amounts of cAMP and thus active PKA. Sympathetic stimulation in vivo increases heart rate as part of the animal’s fight-or-flight response and is controlled at the cellular level by increasing both the amplitude and decay rates of calcium transients. This response was missing in the AKAP5 mutant heart cells, showed the team. Without AKAP5, PKA and a complex of other proteins failed to associate with a particular subpopulation of L-type calcium channels. The authors conclude that this association is responsible for the full-and-fast calcium transients induced by sympathetic stimulation. Chronic stimulation of the sympathetic pathway can lead to hypertrophy and heart failure, raising the question of whether the AKAP5 complex and its associated channel are altered in the patho-physiology of the disease.

    Plasma MicroRNAs in Diabetes (p 810)30

    Zampetaki et al reveal a profile of plasma microRNAs that predict the risk of type 2 diabetes.

    MicroRNAs (miRs) are short chains of 20 to 25 nucleotides that regulate gene expression by binding to target messenger RNAs. It was recently discovered that miRs are not restricted to life inside the cell: they can travel outside, circulating in the bloodstream in small, protective vesicle packages. It has also been discovered that the circulating levels of specific miRs can be altered in certain disease states. A number of miRs have been implicated in the disease process of type 2 diabetes, but heretofore, no one had looked at circulating miRs. Now, Zampetaki et al have. They isolated RNA from blood samples of a random cohort of individuals who had been monitored during a 20-year period. Screening the samples revealed a consistent list of miRs that were differentially expressed between diabetic people and controls. One of the miRs on the list was the blood vessel-promoting miR-126, which was significantly reduced in diabetics. Interestingly, these miRs were predictive of disease, because their levels were altered in normal individuals who later went on to develop diabetes. Using the five most significant miRs, the team successfully identified 92% of controls and 70% of diabetics, highlighting the miRs’ potential usefulness as novel biomarkers.

    PKCα C-Terminal Fragment and Cardiomyopathy (p 903)31

    A suspected degrader of protein kinase C, in fact, liberates the active subunit of the kinase, which wreaks havoc in ischemic hearts, report Kang et al.

    Activation of protein kinase C (PKC) is calcium dependent and normally occurs in response to receptor signaling events. Calcium also activates a protease called calpain 1 that cleaves PKC. Thus, it was thought that calcium both induced PKC signaling and then switched it off by calpain-mediated degradation. According to a new study by Kang et al, however, calpain is not the off-switch. Calpain cleaves PKC in two, releasing the catalytically active C-terminal from the regulatory N-terminal. Far from degrading the enzyme, this cleavage unleashed the C-terminal’s unfettered activity, say the authors. They made their discovery by looking in ischemic heart tissue of mice that overexpressed calpain. Ischemia prompts a dramatic rise in intracellular calcium levels and, thus, boosts the activities of PKC and calpain. Overexpression of calpain under is-chemic conditions led to increased PKC cleavage, as well as to increased myocardial injury. The increased abundance of the active C-terminal caused hyperphosphorylation of normal PKC targets, as well as phosphorylation of many atypical proteins, which might be responsible for the increased ischemic damage. Drugs designed to inhibit PKC activity might, therefore, work best if aimed at the C-terminal, says the team.

    MSCs Stimulate CSCs After MI (p 913)32

    Transferred stem cells can’t take all the credit for repairing damaged tissues—they recruit host cells to do most of the work, report Hatzistergos et al.

    In recent years, there has been much excitement about the potential of transplanted stem cells to mend heart injuries. Bone marrow-derived mesenchymal stem cells (MSCs) have been particularly favored thanks to their capacity for engrafting into, and restoring contractility of, damaged heart tissue. Intriguingly, the ability of MSCs to fix heart injury seems to greatly surpass their ability to differentiate into heart muscle cells. Thus, it has been unclear exactly how these cells repair the infarcted heart. Hatzistergos et al postulated that the MSCs might be recruiting help from within the host. To test this hypothesis, the team produced heart attacks in female pigs and, 3 days later, injected the damaged hearts with MSCs. Sure enough, the MSCs not only engrafted into the hearts and differentiated into muscle cells, but they also stimulated host (endogenous) heart stem cells to proliferate and differentiate. In fact, the MSCs themselves accounted for only about 8% of the new heart cells. The engrafted MSCs made cell-to-cell contacts with the host stem cells, which appears to be important for the repair process, say the authors. Promoting this host-cell interaction, therefore, might be one strategy to optimize stem cell therapies.

    S1P Regulates Myogenic Tone in Heart Failure (p 923)33

    Hoefer et al have unraveled a molecular pathway that maintains vessel constriction in a mouse model of heart failure.

    Heart failure is defined as the inability of the heart to supply adequate blood to the body’s organs and tissues. When a heart is failing, arterial blood pressure increases to ensure sufficient blood perfusion of the organs. However, this increase in arterial pressure could weaken the heart further, as the heart has to pump harder to get blood into the pressurized aorta. Putting a stop to this positive feedback loop of pathology is, thus, a major goal of heart failure therapy. One way that arterial pressure is increased is through vessel constriction. Hoefer et al found that sphingosine-1-phosphate (S1P)—a blood-borne signaling lipid—is a major activator of chronic vessel constriction in a mouse model of heart failure. The team has also identified p38 MAPK as a downstream mediator of the S1P signal, the ultimate target being myosin, a protein that drives the vascular smooth muscle cell contraction. Inhibition of the S1P receptor, or p38 MAPK, prevented vessel constriction in the model mice. Thus, both S1P and p38 MAPK may be two possible drug targets for breaking the vicious cycle of disease.

    Mitochondria and Na+ Channels (p 967)34

    Liu et al suggest a new way to prevent irregular heartbeats: by keeping a lid on mitochondrial ROS production.

    Maintaining a regular heartbeat depends on the correct functioning of the heart cells’ sodium channels. Indeed, syndromes that display aberrant channel function, such as sudden infant death syndrome (SIDS) and Brugada syndrome, are associated with fatal heart arrhythmias. Both SIDS and Brugada syndrome are linked to gene mutations that result in an increase in the levels of NADH. Excessive NADH increases the intracellular production of reactive oxygen species (ROS), which it is believed might structurally damage the sodium channels. Liu et al were interested in discovering the origin of the ROS. Using a variety of chemical inhibitors, they ruled out certain cellular enzymes and molecules as the source and fingered the blame on mitochondria. When mitochondrial ROS production was inhibited, even in the presence of high cytosolic NADH, normal sodium channel conduction was restored. Therapies for SIDS, Brugada, and other arrhythmias have traditionally targeted the dysfunctional sodium channels themselves. The report by Liu et al suggests that an alternative or adjunctive approach might be to block ROS generation by the mitochondria.

    Enhanced Fibroblast–Myocyte Interactions (p 1011)35

    Fibroblasts activated by heart injury do more than just form scars. They also directly interfere with heart cells’ electrical activity, say Vasquez et al.

    After a heart injury, cardiac fibro-blasts are activated and proliferate quickly to mend the damage. The resulting fibrotic scar was thought to affect the electrophysiology properties of the heart indirectly—by forming a boundary between electrically active muscle cells. But Vasquez and colleagues found that the activated fibroblasts are not so passive after all. A critical step in fibroblast activation is their conversion into myofibroblasts. Myofibroblasts differ from the normal cardiac fibroblasts in their proliferative, migratory, adhesive, and collagen-synthesizing capacities. It now appears they differ in their electrical properties, too. The team showed that compared with regular fibroblasts, myofibroblasts formed more connections with cardiomyocytes and altered the myocytes’ conduction velocities and action potential durations. Interestingly, myofibroblast-conditioned culture medium could also affect myocyte electrical activity, indicating that myofibroblasts exert their affect both through cell-to-cell contacts and via secreted factors. Severe arrhythmias can ultimately result in sudden death. Because conversion of fibroblasts to myofibroblasts could potentially distort regular heart rhythm, targeting this conversion could be an effective antiarrhythmic strategy.

    DNA Damage in Atherosclerosis (p 1021)36

    Damaged DNA drives development of atherosclerosis, report Mercer et al.

    DNA damage has been detected in the plaques and circulating cells of patients with atherosclerosis, but whether this damage was a byproduct or the antecedent cause of the disease was unknown. Mercer and colleagues now report data that support the latter possibility. The team showed that mice that were deficient for a DNA repair factor called ATM were prone to accelerated atherosclerosis and to other symptoms of metabolic syndrome, such as hypertension, increased body fat, and glucose intolerance. In the ATM-deficient mice, macrophages and vascular smooth muscle cells (VSMCs)—both of which contribute to plaque formation—displayed increased genomic and mito-chondrial DNA damage, as well as increased reactive oxygen species (ROS) production. Transfer of bone marrow cells expressing wild-type levels of ATM improved the accelerated atherosclerosis phenotype. It did not improve the other symptoms, however, most likely because ATM-deficiency caused mitochondrial DNA damage and dysfunction in other tissues, such as liver and pancreas. Mitochondrial dysfunction might be particularly detrimental in metabolic syndrome progression because failing mitochondria produce excessive ROS, which can further damage DNA and worsen dysfunction. Drugs that reduce DNA damage or boost mitochondrial function, or both, could thus be especially effective in preventing atherosclerotic lesion formation and metabolic syndrome.

    CXCR4 Regulates BM PC Mobilization Through c-kit (p 1083)37

    Two types of cell surface receptors work together to keep progenitor cells tucked away in the bone marrow, say Cheng et al.

    After ischemic injury, certain progenitor cells in the bone marrow become mobilized, enter the peripheral circulation, and home to the injury site to help with repairs. Until needed, however, the progenitors stay where they are, and researchers have identified two molecular mechanisms that keep them tethered. Whether these two mechanisms were at all related was unknown. Both mechanisms involve interactions between cell surface receptors on the progenitors and their ligands on structural cells of the bone marrow. Cheng et al found that interaction between the first receptor, CXCR4 and its ligand, SDF-1, led to phosphorylation of the second receptor, called c-kit. Consistent with this, a drug called AMD3100, which is known to mobilize progenitors by interacting with CXCR4, reduced levels of phosphorylated c-kit. And, in mice that expressed a constitutively phosphorylated mutant c-kit, AMD3100 lost its mobilizing ability. Because progenitor mobilization is a crucial part of ischemic tissue repair, AMD3100 and other experimental treatments are being investigated for their mobilizing potential. Understanding the molecular nature of the process, thus, offers targets for such treatments.

    Timing of Spontaneous Ca Release in Ca Overload (p 1117)38

    Calcium overload in the heart can cause fatal arrhythmias. Wasserstrom et al have discovered how subcellular calcium events coordinate across the muscle to trigger such undesirable beats.

    On a cellular level, the regular beats of the heart start with an electrically triggered action potential that prompts the sarcoplasmic reticulum to release calcium ions that bind to protein machinery that contracts the cell. As well as this controlled calcium release, however, the sarcoplasmic reticulum releases small amounts of calcium spontaneously and apparently stochastically. In conditions of calcium overload, these small calcium release events, or sparks, have been linked with plasma membrane depolarizations that can reach action potential thresholds. For an arrhythmia to occur, however, many cells must work in unison, so it was unclear how stochastic calcium sparks in individual cells could achieve this. Wasser-strom et al measured the spatiotemporal distribution of calcium sparks across muscle cells in intact rat hearts. They found that during calcium overload, the number of sparks increased and the variability in spark timing decreased. This more coordinated timing could, thus, allow cells to simultaneously depolarize, say the authors. They suggest that factors affecting timing, such as SERCA, which reloads calcium into the sarcoplasmic reticulum, could be good targets for antiarrhythmic therapies.

    CaMKII Inhibition in Failing Human Myocardium (p 1150)39

    Inhibiting CaMKII activity could be a means to improve functionality in failing human hearts, say Sossalla et al.

    CaMKII is a protein kinase that regulates many components of the calcium-handling cycle of cardiomy-ocytes. Levels of CaMKII have been reported to be elevated in failing human hearts, but researchers were not sure whether this elevation was some sort of activated compensatory mechanism or whether it was associated with the pathologic process itself. Evidence from mouse and rabbit models of heart failure and from transgenic mice that overexpress CaMKII lent support to the latter possibility. Sossalla et al have now investigated CaMKII’s effects in failing human hearts. CaMKII was, indeed, elevated in both ventricles and was associated with reduced calcium load in the sarcoplasmic reticulum. The authors found that the sarcoplasmic reticulum was releasing more calcium than usual, and this was attributable to increased phosphorylation of a calcium channel, called ryanodine receptor, in the sarcoplasmic reticulum’s membrane. The ryanodine receptor is a known target of CaMKII activity, and inhibiting CaMKII not surprisingly stemmed the calcium leak. More importantly, inhibiting CaMKII also improved contractility in the failing heart tissue. The authors, therefore, suggest that inhibition of CaMKII may be a new strategy in the fight against heart failure.

    PKG Controls cGMP Compartmentation (p 1232)40

    Location is everything when it comes to cGMP regulation, say Castro et al.

    The signaling molecule, cGMP, is produced in heart cells mainly in response to two different vasodilators—atrial natriuretic peptide (ANP) and nitric oxide (NO)—and in two different locations. ANP activates cGMP production at the plasma membrane, whereas NO does it in the cytosol. At both locations, the immediate downstream effector of cGMP activity is the protein kinase PKG. Castro et al have now discovered that in addition to regulating downstream targets, PKG regulates cGMP production itself. And that’s not all: PKG worked differently at the two locations. At the membrane, PKG had a positive feedback effect—stimulating activity of the enzyme that produces cGMP—whereas in the cy-tosol, PKG prompts the breakdown of cGMP by hydrolysis. Thus, under conditions of PKG activation, a steep gradient of cGMP would occur from membrane to cytosol, say the authors. These two different effects of PKG might help to unravel the different mechanisms of action, and the cardiovascular effects, of ANP and NO.

    Collagen XV in Heart and Microvessels (p 1241)41

    Mice that lack collagen XV provide clues to cardiomyopathic processes, report Rasi et al.

    Collagen XV is expressed in the extracellular matrix (ECM) of many tissues and is particularly abundant in the heart. Remodeling of the heart’s ECM occurs during periods of cardiac stress, after injury, or simply as a result of aging. Understanding this remodeling mechanism could, thus, help researchers understand the cardiomyopathic process. The hearts of mice lacking collagen XV displayed a disorganized ECM and decreased elasticity, as well as unusual myocyte structure, and thinner interventricular septums and ventricle walls. The capillaries in the heart were also affected and displayed irregular lu-minal shapes, ruptures in the endo-thelial walls and variations in thickness. Functional analysis revealed that mutant mouse hearts had reduced pumping power, but unexpectedly, this defect improved with age, concurrent with an increase in capillary density and improved myocyte structure. Given that most, if not all, cardiomyopathies are progressive by nature, understanding how the mutant mouse hearts reverse their functional defect could point to an exploitable mechanism for therapy.

    Myomasp/LRRC39, a Novel Sarcomeric M-Band Protein (p 1253)42

    Will et al have identified a novel protein called myomasp, which sits at the M-band of muscle cells and seems to sense how much they stretch.

    The M-band is the region of muscle cells’ sarcomeric structure that acts as an anchor for myosin-containing thick filaments and provides lateral stabilization to the sar-comere. A few M-band proteins have been identified and characterized, but many more remain unknown. Will et al have now identified myomasp. Found during a bioinformatics search for uncharacterized heart- and muscle-specific genes, myomasp was found to be located to the M-band in rat cardio-myocytes and was shown to interact with myosin. Interestingly, when the team knocked down myomasp, known stretch-sensitive genes, called GDF-15 and BNP, were up-regulated. Myomasp knock down also reduced contractile force generation of heart tissue in vitro, impaired heart function, and led to cardiomyopathy in live zebrafish. Certain myopathies are linked with mutations in the region of myosin that interacts with myomasp. Will et al suggest it might be interesting to see whether patients carrying such mutations have altered M-band architecture or myomasp localization. If so, failure to detect overstretching caused by impaired myosin-myomasp interaction could be to blame for these myopathies.

    miR-218 Regulation of Slit-Robo Pathway (p 1336)43

    Small et al have discovered a mi-croRNA that fine-tunes blood vessel development.

    MicroRNAs (miRs) regulate gene expression by binding to target mRNAs and either preventing their translation or tagging them for degradation. Often, one miR can target multiple mRNAs encoding proteins that act in the same molecular pathway. Finding one miR might, thus, offer a means to control expression of an entire network of genes. Small et al decided to look for new miRs that might control cardiovascular development pathways. Within noncoding regions of the genes for Slit2 and Slit3, they found miR-218. Slit is a ligand for a receptor called Robo, and binding of Slit to Robo regulates vascular endothelial cell migration and blood vessel growth. The team discovered that miR-218 targeted and repressed the mRNAs for Robo1, Robo2, and other proteins that control Slit-Robo interactions. Knockdown of miR-218 raised the expression of the target genes and increased human endothelial cell migration. Knockdown of miR-218 in the retinas of newborn mice resulted in aberrant patterning and decreased the number and size of capillaries. The authors now want to check the involvement of miR-218 in various vascular pathologies and tumorogenesis, where regulating angiogenesis would be therapeutically desirable.

    ACE Inhibition Impacts Monocyte Traffic After MI (p 1364)44

    Leuschner et al reveal how a drug for hypertension also helps to prevent heart failure.

    Angiotensin II (Ang II) is an endogenous regulator of blood pressure. It is produced in the blood by angiotensin converting enzyme (ACE), and ACE inhibitors are well-established drugs for treating hypertension. Levels of Ang II increase after myocardial infarction (MI), and Ang II stimulates splenic monocyte mobilization (by binding to receptors on the monocytes). These monocytes enter the blood vessels and are recruited to the infarct to facilitate the healing process. Excessive inflammation can impair the healing process, however, and patients suffering MI often have elevated monocyte numbers and ongoing inflammatory processes as a result of preexisting atherosclerosis. Reducing monocyte recruitment to the infarct is, thus, desirable in such patients. Luckily, ACE inhibitors do just that, Leuschner et al now show. The ACE inhibitor, enalapril, reduced monocyte motility and recruitment, improved heart healing, and reduced potentially fatal ventricle remodeling in a mouse model of MI with preexisting atherosclerosis (ApoE-/- mice). Although the findings do not point to a new form of treatment, they do suggest that monitoring changes in monocyte numbers in post-MI patients might provide a means for assessing healing in the heart after infarction.

    Age, Gender, and Cardiomyogenesis (p 1374)45

    Your heart cells are not as old as you, claim Kajstura et al. In fact by the time you are 100, your cardiomyocytes are no more than a few years old.

    This seemingly paradoxical concept stems from calculations of Kajstura et al of cardiomyocyte turnover rates in relation to aging. The team analyzed postmortem heart tissue from men and women between the ages of 19 and 104 years who had died from causes other than cardiovascular conditions. By mathematical modeling, the team calculated that at the ages of 20, 60, and 100 years, myocytes in the male heart are replaced at rates of 7%, 12%, and 32% per year, respectively. For women, the rates were even higher: 10%, 14%, and 40%. These rates predict that between the ages of 20 and 100 years, the female heart replaces its entire myocyte compartment 15 times and the male heart does so 11 times. In old hearts, old cells were replaced with old cells, as defined by short telomeric DNA. Thus, as hearts age, replacement cells are less functional and progress to senescence and death more quickly, explaining the age-dependent increase in turnover rates. The team observed a small number of stem cells that retained their telomere length, even in aged hearts, however. Whether this pool of genetically youthful cells could be therapeutically activated to replace aged or damaged heart tissue will be an interesting possibility to investigate in the future.

    Macrophage ABCA1 and SR-BI in Atherogenesis (p e20)46

    Zhao et al report that two fat-shifting factors work synergistically to keep macrophages healthy and atherosclerosis at bay.

    Despite their voracious appetite, macrophages are unable to fully digest the lipids they ingest. Instead, they rely on factors, such as ABCA1, to export excess cholesterol out of the cell. Lipid accumulation inside macrophages can result in their transformation into foam cells that give rise to atherosclerotic plaques. Indeed, loss of ABCA1 from macrophages has been reported to increase atherosclerotic lesion formation. SR-B1 is another macrophage cholesterol exporter, but it also promotes cholesterol uptake by the liver. Deletion of SR-B1 from macrophages both enhances progression of advanced atherosclerotic lesions and inhibits development of early lesions. Zhao et al wondered what would happen if SR-B1 and ABCA1 were deleted together. They discovered that in atheroscleroticprone mice, macrophage-specific deletion of SR-B1 alone caused a large increase in serum cholesterol, whereas deletion of ABCA1 caused a decrease. When both factors were deleted together, serum cholesterol levels were decreased even further. Combined deletion also increased the formation of foam cells and of atherosclerotic lesions. Therefore, a two-pronged approach at increasing these factors’ activities might be an avenue for antiatherosclerotic therapies.

    Endothelial NO Modulates APP Expression (p 1498)47

    Austin et al suggest why cardiovascular risk factors are also risk factors for Alzheimer disease (AD). The common culprit, they say, is a lack of nitric oxide.

    Although the precise cause of AD remains unclear, it is well known that high blood pressure, high cholesterol, diabetes, aging, and a sedentary lifestyle are all risk factors. Furthermore, in addition to AD’s classical pathologic features, such as the deposition of amyloid β protein in extracellular plaques and the formation of intracellular tangles of τ protein, vascular endothelial dysfunction is common. Vascular function and homeostasis are regulated, in part, by the signaling molecule nitric oxide. Indeed, nitric oxide-deficient mice suffer from high blood pressure and insulin resistance. Interestingly, the brains of these mice also display features of AD, Austin et al now show. Nitric oxide-deficient brain tissue exhibited increased expression of a protein called APP and an enzyme called BACE, which converts APP into plaque-forming amyloid β.In vitro studies further revealed that when nitric oxide was low, increasing expression of its downstream target, cGMP, could bring levels of BACE and APP back down. Therefore, the authors suggest that boosting the nitric oxide/cGMP pathway might prevent symptoms of AD.

    hERG and Reentry (p 1503)48

    Hou et al reveal how increased expression of a particular potassium channel maintains deadly ventricular fibrillation.

    Rapid, irregular, and unsyn-chronized contraction of the heart leads to fibrillation, which, not surprisingly, can be fatal. Electrical waves called reentrant waves, or rotors, are known to sustain ventricular fibrillation, but the molecular mechanisms that contribute to the development of rotors are not well understood. It is suspected that the rectifier potassium current—that which repolarizes the heart cells at the end of the action potential— might play a role. Hou et al, therefore, investigated whether an increase in expression of hERG—the channel regulating the rapid delayed rectifier potassium current—could affect the frequency, stability, and duration of these rotors. They found that rat ventricular monolayers expressing high levels of hERG had dramatically accelerated rotor frequency. This, say the authors, was due to considerably shorter action potential duration and increased excitability. Gain of function mutations of hERG have been linked to an inherited fatal arrhythmia disorder. Therefore, regulating hERG activity may be a useful therapeutic intervention for controlling fatal arrhythmias.

    Circulation Research, vol 108, 2011

    Mitochondrial Fusion in Drosophila Hearts (p 12)49

    Fusion of mitochondria is essential for function in cardiac myocytes, report Dorn et al.

    Mitochondria periodically get together to exchange their contents. They do this by fusing both their inner and outer membranes under the control of particular membrane-bound proteins. The role of mitochondrial fusion in cardiomyocytes, where mitochondria make up a whopping 30% of the total volume, is not yet known. To investigate this, Dorn et al used RNAi to knock down the expression of two mi-tochondrial membrane-bound fusion regulators in the cardiac cells of flies. They found that loss of either protein led to defective fusion events—mitochondria were more heterogeneous in morphology and were, on average, approximately 30% smaller than in wild-type cells. Furthermore, the heart tube itself was dilated and displayed impaired contractility, suggesting that mi-tochondrial fusion is required for normal heart cell function. The defects could be prevented by excess superoxide dismutase, however. Because this enzyme removes reactive oxygen species, the authors conclude that free radicals are the damaging byproducts of the defective fusion events. In conclusion, proper mitochondrial fusion appears to be essential for preventing dilated cardiomyopathy in flies and, thus, perhaps in humans, too.

    RISC Sequencing and In Vivo miR Targets (p 18)50

    In the hunt for heart-specific mi-croRNA targets, Matkovich et al have refined their hunting tactics.

    MicroRNAs (miRs) are small non-coding RNAs that bind to target mR-NAs and suppress their expression by either tagging them for destruction or preventing their translation. In many cases, a single miR is capable of suppressing multiple mRNAs in the same cellular pathway, making them attractive target kingpins for therapies. Accurately identifying miR target mRNAs is not straightforward, however. Isolating target mRNAs from RISC—the protein complex where miRs and mRNAs in-teract—is one recently developed technique. But, the method requires the isolated mRNAs to be amplified before identification, which, say Matkovich et al, favors the isolation of certain mR-NAs over others. The team has now refined the technique to avoid this amplification step, thus removing the bias. To find mRNAs associated with specific miRs, the team overexpressed cardiac-specific miR-133a and miR-499 in mouse hearts and used their new improved tool to compare RISC-associated mRNAs with total cell mR-NAs. They identified 209 in vivo targets for miR-133a and 81 targets for miR-499. The new technique should be useful not only for identifying targets of native miRs, but also those of miRs designed for therapies, say the authors.

    HKII in Ischemia/Reperfusion Injury (p 60)51

    Boosting glucose metabolism could help injured hearts to recover, say Wu et al.

    It is well known that heart cells switch from fat metabolism to sugar metabolism (glycolysis) to increase available energy after ischemic injury. Wu et al, therefore, wondered whether altering the levels of glycolytic enzymes might affect recovery. One of the key rate-limiting enzymes of glycolysis is hexokinase (HK), of which four different isoforms exist in mammals—I, II, III, and IV. HKII is primarily expressed in both heart and skeletal muscle, so Wu and colleagues decided to start with this one. The team observed how HKII-deficient mouse hearts and wild-type mouse hearts, which are of similar size and function under normal conditions, fared after suffering an ischemic injury. HKII-deficient hearts were much worse off, displaying considerably reduced contractility and output after ischemia compared with wild-type hearts. This reduction in function was confirmed in isolated heart cells, in which a lack of HKII resulted in reduced ATP levels and contractility. HKII-deficient mice also suffered more extensive heart injury compared with wild types, with greater cell death and fibrosis and reduced postinjury angiogenesis. The authors suggest that increasing levels of HKII might be a new therapeutic option for decreasing ischemic injury to the heart.

    ERK1/2 and Length/Width Growth (p 176)52

    Whether heart cells grow wide or long depends on ERK1/2 signaling, say Kehat et al.

    Many studies implicate ERK1/2 signals in cardiac hypertrophy, but mouse models designed to overexpress or lack ERK1/2 have provided seemingly contradictory results. Overexpression leads to a type of hypertrophy called concentric hypertrophy, in which the heart cells thicken, but genetic deletion of ERK1/2 does not stop the heart from enlarging. Kehat et al now resolve the issue by showing that ERK1/2 controls the way heart cells grow. Without ERK1/2, heart cells lengthened rather than thickened. Such growth was apparent in the hearts of the transgenic mouse models, as well as from heart cells in culture in which ERK1/2 expression was acutely controlled. This suggests ERK1/2’s effects are direct rather than secondary, say the authors. Pressure overload in the heart tends to make heart cells thicken, whereas volume overload tends to lengthen them. Con-fusingly, both types of hypertrophic stimuli activate ERK1/2. One possible explanation is that although ERK1/2 simply promotes cell thickening, it loses the battle to length-promoting signals in situations of volume overload. Because pathologic hypertrophy can lead to heart failure and death, discovering ERK1/2’s downstream targets and precisely how it controls the hypertrophic response could ultimately save lives.

    ABC Transporters in Macrophage Migration (p 194)53

    Pagler et al show how good cholesterol (HDL) promotes macrophage migration away from atherosclerotic plaques.

    Atherosclerotic plaques are formed in part by the accumulation of foam cells—macrophages and smooth muscle cells carrying excessive amounts of bad cholesterol (LDL). HDL helps clear LDL from foam cells by the action of the fat-transporting proteins, ABCA1 and ABCG1. HDL thus helps to prevent the formation of atherosclerotic plaques or to remove plaques that have started to form. Plaque reduction, or regression, is associated with migration of macrophages away from the plaque toward local and systemic lymph nodes. Pagler et al wondered whether HDL and ABCA1/G1 were also controlling this migration. In vitro migration assays showed that wild-type macrophages moved in response to HDL, but ABCA1/G1- lacking macrophages did not budge. The team further showed that in the ABCA1/G1-lacking cells, sterols accumulated at the cytosolic face of the plasma membrane and, in turn, activated Rac1, a signaling molecule that controls many cellular functions including cytoskeletal reorganization and cell motility. Boosting HDL has been suggested as a therapeutic intervention to stop and reverse atherosclerosis. Pagler et al show, at least in part, how such therapy would work.

    Quarky Ca2+ Release (p 210)54

    Size might not be everything when it comes to calcium-release events, report Brochet et al.

    In a heart cell, calcium release from the sarcoplasmic reticulum (SR) occurs in discrete events called sparks. Calcium is released from the SR via membrane channels called ryanodine receptors, which are organized into clusters called calcium release units (CRUs). It was thought that under normal physiologic conditions, sparks were the only mode of calcium release event, but recent evidence suggests that smaller events dubbed “quarks” might also exist. Because such low-level release events are hard to resolve from the noise, Brochet et al took a novel approach of simultaneously measuring drops in calcium level inside the SR (blinks), as well as their corresponding cytosolic sparks. This enabled the detection of “true” release events and, importantly, confirmed the existence of quarks. Although the amount of calcium released by quarks as tiny compared with sparks, quarks were much more frequent, thus overall their contribution to calcium release was similar. The authors suggest that quarks might arise from rogue ryanodine receptors, those spatially separated from CRUs. Whatever their source, because faulty calcium-release events underlie potentially fatal arrhythmias, understanding the mechanisms and the effects of quarks will be important for the future of arrhythmia research and treatment.

    NCAM1 Variant & LV Wall Thickness (p 279)55

    A particular variant of the NCAM1 gene poses a risk for left ventricular hypertrophy, report Arnett et al.

    Cardiac hypertrophy can, in some cases, lead to cardiac remodeling and, ultimately, heart failure and death. Like many other complex diseases and traits, multiple genetic factors contribute to cardiac hypertrophy. One way to search for genetic variants that might contribute to such complex diseases is to perform genome-wide association studies. And that is just what Arnett et al decided to do. They screened hypertensive African-American families and looked for associations between particular genetic variants, called SNPs (single nucleotide polymorphisms), and electrocardiographic indicators of hypertrophy, including left ventricular (LV) mass, wall thickness, and internal dimension. They found a SNP in the first intron of the gene for NCAM1 that showed strong association with LV hypertrophy. The authors confirmed this association in a screen of white hypertensive families. NCAM1 has previously been shown to be upregulated in the hypertrophic hearts of rats. Thus, although it is not yet clear how this human genetic variant leads to a risk for hypertrophy, the current study implicates NCAM1 in the genesis of this syndrome.

    miR-98/let-7 Inhibits Cardiac Hypertrophy (p 305)56

    Yang et al uncover a new microRNA-based mechanism by which thioredoxin 1 inhibits cardiac hypertrophy.

    Thioredoxin (Trx1) is a ubiquitously expressed antioxidant protein with a wide variety of cell-protective functions. Among these is its ability to inhibit pathologic cardiac hypertrophy by a mélange of molecular mechanisms. Yang et al have now discovered yet another mechanism to add to the mix involving microRNA -98 (aka let-7). MicroRNAs, or miRs, are small noncoding RNAs that either translationally suppress or degrade target mRNAs. A number of miRs have been reported to affect cardiac hypertrophy, so Yang et al wondered whether Trx1 might regulate any of them. The answer was no. However, a new candidate miR—miR-98—was affected by Trx1. In mouse hearts overexpressing Trx1, miR-98 was significantly upregulated. Overexpression of miR-98 itself in heart cells inhibited Ang II-induced hypertrophy. One predicted target mRNA of miR-98 is cyclin D2, which has been independently implicated in cardiac hypertrophy. The authors showed that miR-98 suppressed the expression of cyclin D2, which in turn inhibited cardiomyocyte hypertrophy. The discovery of the Trx1/miR-98/cyclin D2 pathway offers researchers new tools in the search for antihypertrophic therapies.

    S1P3 and Macrophages in Atherosclerosis (p 314)57

    Keul et al discover a means to keep macrophages minimal in atherosclerotic plaques.

    Macrophages migrate to atherosclerotic lesions as part of the pathologic process that leads to plaque growth. A known promoter of immune cell migration is a bioactive lipid called S1P, found in blood plasma and tissue fluids. Interestingly, S1P serum levels in humans display a positive correlation with severity of coronary artery stenosis (narrowing), suggesting that S1P may be involved in the pathogenesis of atherosclerosis. In apparent contrast to this result, however, an analog of S1P inhibits atherosclerosis in mice. Keul et al realized that the analog experiments did not differentiate between the possible separate effects of S1P’s many cell surface receptors. The team decided to investigate what would happen when one particular S1P receptor, S1P3,is absent. Their in vitro experiments showed that S1P chemoattracted wild-type macrophages but not those lacking S1P3. Furthermore, atherosclerosisprone mice that lacked S1P3 had less macrophages at their atherosclerotic lesions. Lesion size, however, was not affected. Instead, the lesions contained increased numbers of smooth muscle cells. Although the mechanism behind this remains unclear, an increase in smooth muscle cells suggests an increase in plaque stability. The authors suggest that specific inhibition of S1P3 might be a useful strategy to reduce inflammation in atherosclerotic lesions.

    Endothelial Activation by Shear Stress (p 410)58

    Fu et al report how two atherosclerosis risk factors synergistically activate one molecular mechanism in vascular endothelial cells.

    Both disturbed blood flow and high cholesterol are known to promote the formation of atherosclerotic plaques in blood vessels. Previous work by this research team had shown that high cholesterol prompts the endothelial cells lining the blood vessels to increase their surface expression of a molecule called ATPSβ. This molecule binds to γ/δ T cells, which are enriched at early-stage atherosclerotic plaques. The team has now discovered that the surface expression of ATPSβ is increased by disturbed blood flow as well. ATPSβ is found within the cell associated with mitochondria, as well as at the cell surface, but both disturbed blood flow and high cholesterol promoted the molecule’s recruitment to lipid rafts, which translocated it to the membrane. The γ/δ T cells recruited by increased ATPSβ cell surface expression released inflammatory cytokines. These cytokines caused further activation of the endothelial cells, leading to an increase in the proinflammatory cell adhesion molecule—VCAM-1. Since cell surface ATPSβ expression appears to set off a chain inflammatory reaction, perhaps blocking its translocation might be investigated as a means to slow atherosclerosis.

    IPC-Induced Protein SNO Protects Against Oxidation (p 418)59

    Nitric oxide protects cardiac proteins from permanent oxidative damage by getting in the way, say Kohr et al.

    Part of the tissue damage caused by cardiac ischemia is the result of a sudden burst of reactive oxygen species (ROS). Damage can be reduced if the heart experiences a brief ischemic attack before a more serious prolonged one, in a process called preconditioning. It is known that nitric oxide (NO) plays a role in the cardioprotective mechanisms of preconditioning, and one way it is thought to do so is by S-nitrosylation—the addition of nitric oxide (NO) moieties to proteins. The hypothesis is that protein nitrosylation, which is a reversible modification, prevents the more damaging irreversible modification of proteins by oxidation. Nitrosylation can be measured by a technique called SNO-RAC (resin-assisted capture). Here, Kohr et al have modified this method to measure nitrosylation and oxidation simultaneously (SNO-RAC/Ox-RAC). After preconditioning mouse hearts, the team found that the level of S-nitrosylation was increased in 27 proteins. Furthermore, 76% of these proteins showed decreased oxidation after ischemia/reperfusion injury compared with proteins that had not been exposed to preconditioning. Kohr et al, thus, provide one more piece of the preconditioning puzzle that might be exploited for cardioprotective therapies in the future.

    GSK-3/β Improves Mesenchymal Stem Cell Therapy (p 478)60

    Cho et al have found a way to boost the heart-fixing benefits of bone marrow-derived stem cells.

    Many stem and progenitor cell types have been investigated for their potential to promote tissue regeneration and to repair injured hearts. Although bone marrow-derived mesenchymal stem cells (BM-MSCs) have shown particular promise, there is still room for improvement. BM-MSCs do not differentiate efficiently into cardiomyocytes in vivo and, thus, do not contribute to repair as much as they potentially could. Cho and colleagues recently found that a kinase called GSK-3β, which activates a variety of intracellular proteins and pathways, can increase cardiac-specific gene expression in BM-MSCs in vitro. With this in mind, the team looked to see whether pretreating BM-MSCs with GSK-3β would improve their ability to differentiate and, thus, repair heart injury in vivo. It did. In mice that had suffered heart attacks, injection of GSK-3β BM-MSCs improved survival rates compared with injection of control BM-MSCs. Left ventricular function was improved, remodeling was reduced, and capillary density was increased. Improved survival and capillary density were both dependent on the growth factor VEGFα, which was upregulated by GSK-3β. Interestingly, however, ventricular function and reduced remodeling were not. Clearly, there are VEGFα-independent mechanisms of GSK-3β action, but whatever those are, this kinase could provide a much-needed boost to cardiac regenerative therapies.

    Regulation of Ito f by NF-κB (p 537)61

    Panama et al suggest a way to keep cardiac potassium efflux efficient and, thus, to maintain cardiac function during heart disease.

    Efflux of potassium ions after rapid depolarization mediates repolarization of the heart. This potassium efflux is invariably impaired in heart disease and hypertrophy, but little is known about the molecular mechanisms responsible for this malfunction. Activation of vasoconstricting α1-adrenergic receptors is known to reduce potassium efflux, as is the inflammatory cytokine tumor necrosis factor (TNF)-α known activator of a transcription factor called nuclear factor (NF)-κB. Panama et al were particularly interested in NF-κB, because it is activated in heart disease patients and animal models of hypertrophy and heart failure. The team found that, like TNF-α, α-adrenergic receptor stimulation also activated NF-κB and that, in turn, NF-κB repressed the expression of a potassium channel auxiliary factor called KChIP2. Lack of available KChIP2 would limit the assembly of necessary potassium channels and reduce potassium efflux, say the authors. Because inhibiting NF-κB prevented the effects of α1-adrenergic receptor stimulation on potassium efflux, this factor might be a possible target for heart disease and hypertrophy therapies in the future.

    Integrin αMβ2 Regulates Monocyte Activation (p 544)62

    Making macrophages stickier impairs their transformation into atherosclerosis-promoting foam cells, say Yakubenko et al.

    Infiltration of monocytes and their activation and transformation into fat-gobbling foam cells is a key step in the development of atherosclerotic lesions. Activation of monocytes to macrophages occurs by classical and alternative pathways, and both are implicated in atherogenesis. In this study, the authors focused on the process of alternative activation (by interleukin [IL]-4 and 1L-13). They showed that alternative activation of monocytes induced expression of a foam cell marker called CD36, but that prior stimulation of the monocytes’ β2 integrin receptors inhibited this induction. Integrins are cell surface receptors that bind extracellular matrix components. When stimulated, integrins promote the adherence of monocyte to vascular endothelial cells and their migration toward sites of inflammation, such as atherosclerotic plaques. The finding that integrin stimulation was also antiatherogenic (by preventing foam cell formation) was, therefore, somewhat unexpected. The team confirmed the result, however, by showing that mouse monocytes lacking αMβ2 integrins converted more readily to foam cells (at alternative activation) than did wild-type monocytes. Unexpected or not, the finding suggests that integrin stimulation might be a handy adjunct to antiatherosclerotic therapies.

    ROS Activate CaMKII to Regulate Late INa (p 555)63

    Wagner et al discover a new mechanism of sodium imbalance in failing hearts.

    The generation of reactive oxygen species (ROS) at sites of ischemia can wreak havoc on the cardiac tissue. Part of the problem is that the ROS lead to loss of sodium and calcium homeostasis, which in turn can lead to contractile dysfunction, arrhythmias, and heart failure. ROS are known to cause accumulation of sodium and calcium in heart cells, but it was not entirely clear how. Wagner et al suspected that a kinase called CaMKII might be involved, at least in the sodium increase. This kinase can activate sodium channels and displays increased expression during heart failure. Furthermore, ROS can oxidize and activate the regulatory domain of CaMKII. The team has now put the pieces together and shows that ROS-induced increase in sodium was, indeed, dependent on CaMKII. Activation of CaMKII by ROS, however, was dependent on ROS-induced calcium release from the sarcoplasmic reticulum. This is because ROS cannot oxidize CaMKII until calcium binds to the kinase and opens up its regulatory domain. The authors suggest that the calcium release occurs through channels called RyRs, which ROS are known to activate. They also suggest that the ROS-activated CaMKII pathway might be a good target for heart failure treatments.

    Role of Gabl in Postnatal Angiogenesis (p 664)64

    Blood vessels get growing with Gabl, report Shioyama et al.

    Grb2-associated binder 1 (Gab1) is an intracellular protein that amplifies signals triggered by extracellular factors, such as cytokines, antigens, and growth factors. Shioyama et al wondered whether blood vessel development, a process regulated by growth factors, might therefore require Gab1. Mice that lack this protein die as embryos, having failed to properly develop organs, such as the heart, skin, and muscle. The team thus removed Gab1 specifically from mouse vascular endothelial cells to see if blood vessel growth was impaired. It was. Newborn wild-type mice that had their femoral arteries ligated to induce hind limb ischemia underwent a period of angio-genesis after ligature removal, but the hind limbs of mice lacking endothelial cell Gab1 did not similarly recover. Although a number of growth factors promote angiogenesis, the team showed that HGF was the main activator of Gab1. HGF treatment induced Gab1 phosphorylation and promoted the association ofGab1 with signaling factors and downstream activation ofGab1 target genes. Gab1 could, thus, become a target for pro- or antiangiogenic therapies of the future.

    PM Induces Inflammation via TLR4 Pathways (p 716)65

    Kampfrath et al show how chronic air pollution puts us at risk for cardiovascular disease.

    Inhalation of airborne particulates is known to be bad for our health. As well as causing lung problems, air pollution is also associated with an increased risk of cardiovascular diseases, such as atherosclerosis. It has been proposed that inflammatory responses in the lungs lead to the development of secondary systemic inflammation, which causes the cardiovascular problems, but the mechanisms behind this inflammation are unknown. Kampfrath et al have shown that fluid from the lungs of mice exposed chronically to airborne particles had increased levels of oxidized phospholipids. These molecules induced both inflammatory gene expression and cytokine production in monocytes. Monocytes lacking the cell surface receptor called TLR4, however, were resistant to the oxidized phospholipid effect. TLR4 deficiency also attenuated the rise in peripheral monocyte numbers seen in wild-type animals in response to chronic particle exposure. Reactive oxygen species production by these monocytes was also reduced. TLR4 is a member of a family of receptors that recognize a broad array of environmental and pathogenic antigens and that act as a first line of host defense. Here, Kampfrath et al suggest how this front line molecule could potentially amplify localized lung inflammation to become systemic after chronic air pollution exposure.

    Human Resistin Stimulates Hepatocyte ApoB (p 727)66

    Block resistin to lower bad cholesterol, say Costandi et al.

    Overweight individuals are at risk of atherosclerosis, in part, because of dyslipidemia, which is an overabundance and imbalance of lipids in their bloodstream. This imbalance is primarily due to an increase in the amount of low-density lipoproteins (bad cholesterol) relative to high-density lipoproteins (good cholesterol). Elevated levels of low-density lipoprotein (LDL) are correlated with high plasma levels of resistin, a factor secreted from fatty tissue. Experiments in mice have shown that high plasma resistin can directly boost LDL levels. Costandi et al were concerned, however, that these experiments had used unphysiologic levels of resistin. What’s more, they say, it cannot be assumed that mouse and human resistin behaves the same way; indeed, the human and mouse resistin genes differ considerably. The team, thus, studied the effect of physiologic levels of human resistin on human hepatocytes. Their experiments supported the results seen in mice and also pointed to the mechanisms involved in increased LDL production. Resistin increased the activity of a protein called MTP, which loads LDL onto apoB (the plasma LDL transporter), and it reduced insulin signaling, known to enhance apoB stability. Although further details of these mechanisms are yet to be discovered, the results indicate that reduction in resistin activity might lead to lower LDL levels and, thus, a lower risk of atherosclerosis.

    Intramyocardial Stem Cell Injections in Patients (p 792)67

    Preliminary clinical trial data suggest that bone marrow cells can fix damaged hearts, report Williams et al.

    After a heart attack, scarring to the cardiac muscle reduces its contractility and can lead to heart enlargement (hypertrophy) and failure. Recent research has focused on attempts to repair such damage by cell replacement therapy. A number of different cell types have been tried, and bone marrow-derived progenitors are a favorite due to their relative accessibility and differentiation capacity. However, injections of bone marrow progenitors into patients’ hearts have shown only modest improvements in the ejection fraction of the heart. Williams et al now report that ejection fraction might not be the best parameter to measure functional improvement. Using state of the art imaging technology to assess different parameters, they found that bone marrow-derived progenitors work better than thought. Eight patients’ hearts were injected with progenitor cells derived from their own bone marrow, and after just 3 months, improvements were observed in infarct size and contractility. By 6 months, improvements in the chamber dimensions of the hearts were also seen, suggesting that reverse remodeling had occurred. This reduction in chamber volumes might, in part, account for the apparently modest improvement in the ejection fraction, say the authors. Encouragingly, these results pave an optimistic path for future bone marrow progenitor trials.

    Arcuate Leptin Receptor and Sympathetic Traffic (p 808)68

    Harlan et al pinpoint the brain site at which the fat hormone leptin controls blood pressure.

    Leptin, released from body fat, regulates several physiologic responses, including the suppression of appetite, increase in brown adipose tissue (BAT) metabolic activity, and increase in blood pressure. Interestingly, while the ability of leptin to suppress appetite is dampened in obese individuals, its ability to elevate blood pressure and BAT metabolism is not. The main center for leptin activity in the brain is a region of the hypothalamus called the arcuate nucleus. This nucleus contains a high concentration of leptin receptors and has been shown to be responsible for appetite suppression. However, leptin receptors are found elsewhere in the brain and so it has been proposed that the blood pressure and BAT activity might be controlled remotely. Harlan et al have now found that this is not the case. The team selectively deleted leptin receptors in the arcuate nucleus and found that sympathetic nerve responses in BAT and kidney (site of blood pressure control) were abrogated. Furthermore, in obese mice, high blood pressure was resolved by arcuate-specific removal of the leptin receptor The question of why some but not other responses to leptin are dampened in obesity remains, of course, but Harlan et al have certainly narrowed the search for the answer.

    Cardiac Stem Cells and End-Stage Heart Failure (p 857)69

    Tiny heart biopsies can provide useful numbers of functionally competent cardiac stem cells, say D’Amario et al.

    In the human heart, two types of cardiac stem cells (CSCs) have been identified: myogenic CSCs, which give rise to cardiomyocytes, and vascular CSCs, which give rise to vascular en-dothelial and smooth muscle cells. These CSCs do not intrinsically make a significant contribution to repair after infarction because, it is thought, they do not exist in large numbers in the adult heart. Hence, it is thought that if sufficient numbers of CSCs could be isolated, expanded, and transferred back to damaged hearts, they might significantly boost repair. D’Amario et al decided to test the first two steps in this process—isolation and expansion—to see if such an approach would be feasible. When heart failure patients were undergoing surgery, tiny heart tissue biopsies, estimated to contain just 100 CSCs, were taken. Cells from these biopsies were dissociated, expanded, and sorted to isolate CSCs. After 30-40 days in culture, 5 X 106 mCSCs and vCSCs were obtained. These CSCs could differentiate into muscle or vascular cells, confirming their functionality. Although the remaining step-transferring cells back to the patient will be the proof of the pudding, this important study attests to the feasibility of obtaining sufficient CSCs for clinical trial.

    Echocardiography Strain Analysis in Mice (p 908)70

    A new echocardiographic technique for mice provides a better picture of heart function, report Bauer et al.

    The standard procedure for assessing cardiac function in vivo is echocardiography, but this technique has limited resolution in humans, let alone small-model organisms like mice. Recently, two techniques have been developed to improve the accuracy of echocardiographic imaging in humans: strain analysis, which measures the change in size of particular heart regions, and speckle-tracking, in which specific small features (speckles) are tracked from frame to frame to improve the accuracy of strain measurements. Together, these techniques could also offer a feasible approach for accurate cardiac functional analysis in mice. To test this, Bauer et al induced heart attacks in adult mice and then measured cardiac function using the new techniques. Left ventricular measurements were considerably more sensitive using speckle-tracking strain analysis than standard echocardiography. Furthermore, the new techniques could detect subtle improvements following therapy as soon as two weeks after treatment; whereas standard echocardiography did not detect improvement even after six weeks. The ability to quickly and accurately measure cardiac function in mice will enable not only accurate assessment of new cardiac therapies, but also detection of subtle phenotypic differences between genetic model strains.

    Hand2 Plays a Novel Role in Epicardiogenesis (p 940)71

    Barnes et al have uncovered a new role in cardiogenesis for the transcription factor, Hand2.

    Hand1 and Hand2 are critical transcription factors for the correct development of the vertebrate heart. The two related factors are largely responsible for the morphogenesis of separate tissues and structures in the heart and only partially overlap in their expression pattern. Indeed, although mouse knockouts of either factor both die at around day 9.5 of embryogenesis, they display factor-specific tissue defects. Barnes et al were most interested in the heart cells in which Hand1 and —2 expressions do overlap. They devised a Hand1-specific Hand2 knockout—that is, the knockout of Hand2 only occurred in cells expressing Hand1. Importantly, these embryos survived until day 14.5 of embryogenesis, allowing Hand2’s role to be assessed later in development. Mice with this conditional knockout failed to develop a proper epicardium and coronary vasculature (which is formed, in part, from epicardial cells). This role in epicardial development was hitherto unknown for Hand2. Given Hand1’s and — 2’s essential role in cardiogenesis, the two factors and their pathways are implicated as mediators of congenital heart disease. The study by Barnes et al thus offers further insight into the factors’ normal functions in cardiogen-esis and possible ways the process could go wrong.

    Atherosclerotic Plaque Alternative Macrophages (p 985)72

    Chinetti-Gbaguidi et al identify a population of macrophage do-gooders at atherosclerotic plaques.

    As part of the pathologic process of atherosclerosis, monocytes infiltrate the plaque and develop into specialized fat-filled macrophages, called foam cells. Although foam cells are not problematic individually, their accumulation is detrimental, and it contributes to plaque growth and local inflammation. Monocyte-to-macrophage development can occur by both classic and alternative pathways. Classic activation produces M1 macrophages, which are known to be capable of developing into foam cells. Alternative activation produces M2 macrophages, which have also been found at plaques, though their function there was unknown. Chinetti-Gbaguidi et al discovered that M2 cells at atherosclerotic plaques had far less proclivity for foam cell formation and contained far less fat. Instead, their main occupation seemed to be phago-cytosis—they gobbled up more apo-ptotic cells and debris than their M1 counterparts. Unlike M1 cells, M2 cells are known to produce antiinflammatory signals. Thus, the presence of these antiinflammatory, foam cell-resistant, phagocytosing M2 macrophages at atherosclerotic plaques could well be beneficial. Perhaps boosting their numbers may be a therapeutic avenue worth investigating.

    Peptide Interference of CaM-Cyclin E Interactions (p 1053)73

    Hui et al have designed a small peptide that could help prevent restenosis after angioplasty.

    Following angioplasty to fix a narrowing artery, it is often the case that renarrowing, or restenosis, occurs. A major cause of restenosis is the proliferation of vascular smooth muscle cells (VSMCs). Preventing such proliferation has, thus, been considered a promising avenue of therapeutic investigation. Because their research suggested that VSMC proliferation depends on the binding of calmodulin to cyclin E, Hui et al designed a peptide that would inhibit this interaction. When this 22-amino acid peptide, based on the cal-modulin binding sequence of cyclin E, was transfected into VSMCs, it inhibited cell cycle progression. The team initially electroporated the peptide into cells, but once they had established its success, they switched to a therapeutically feasible delivery system—fusing their peptide to the TAT protein of human immunodeficiency virus, which enters cells with high efficiency. The TAT fusion peptide not only stopped proliferation of mouse and human cells in culture, it also limited neointima formation (vessel wall thickening) in a mouse model of arterial injury. The authors suggest that such a fusion pep-tide could be introduced at the time of angioplasty in the form of a drugeluting stent and, thus, prevent local VSMC proliferation for a prolonged period of time.

    Primary Cilia and Shear-Induced EndoMT (p 1093)74

    The presence of primary cilia prevents vascular endothelial cells from switching to a mesenchymal fate, report Egorova et al.

    Primary cilia are thought to function as mechanosensors for cells. Indeed, vascular endothelial cells (ECs) maintain their primary cilia in areas that are prone to blood flow oscillations, and these cilia are lost in cells exposed to consistently high blood flow. This lack of primary cilia corresponds with the transdifferentiation of ECs into mes-enchymal cells during the so-called endothelial-to-mesenchymal transition (EndoMT). Exactly how the absence of cilia is related to EndoMT, however, was unclear. Egorova et al looked at mutant ECs lacking cilia and found that they readily underwent shear stress-induced EndoMT, whereas wild-type, ciliated ECs did not. The team also showed that this EndoMT was dependent on increased signaling by tumor growth factor (TGF)- β, as well as downregulation of the transcription factor Klf4 within the ECs. Blocking TGF-β, overex-pressing Klf4, or indeed restoring the primary cilia by replacing the mutant protein prevented EndoMT. The authors suggest that the fact that ECs change their fate in the absence of primary cilia may provide clues to the cardiovascular defects often associated with ciliopathies.

    Calcifying Cells and Diabetic Vasculopathy (p 1112)75

    Fadini et al have named and shamed cellular culprits of vascular calcification.

    Vascular calcification, which causes blood vessel stiffness and can destabilize atherosclerotic plaques, is a hallmark process of diabetic vasculopathy. The mechanisms underlying calcification are not well understood, but a type of circulating cell with osteoblastic (bone- forming) characteristics has been identified as the potential culprit. Fadini et al have now confirmed this suspicion by showing the procalcific activity of these cells both in vitro and in vivo. They also discovered that the cells expressed markers specific to the myeloid lineage, and so they gave them the name myeloid calcifying cells (MCCs). Interestingly, MCCs were present in higher numbers in the bone-marrow, blood, and surgically removed atherosclerotic plaques of diabetic patients vs controls. But importantly, the high numbers of circulating MCCs could be reduced to near normal levels in diabetic patients after three months of monitored glucose control (insulin plus oral agents). MCC numbers were also high in nondiabetic patients with cardiovascular disease. Hence, it is possible that targeting procalcific MCCs could be a useful therapy for preventing cardiovascular problems in high-risk individuals, whether diabetic or not.

    RasGRP3 and Diabetic Embryonic Vasculopathy (p 1199)76

    Randhawa et al suggest a means to protect embryos of diabetic mothers from developing vascular defects.

    Babies born to diabetic mothers run a risk of having cardiovascular birth defects, and the severity of such defects correlates with maternal blood glucose levels. The molecular pathway from high maternal blood sugar to abnormal fetal vascular development is murky, but certain molecular players, including diacylglycerol and RasGRP3, are suspected to be involved. RasGRP3 is an intracellular signaling molecule expressed in developing blood vessels and is also activated by diacylglycerol (a cellular membrane lipid). Furthermore, diacylglycerol is known to be elevated in diabetic patients and animals. Rand-hawa et al have now put the pieces together and shown that diacylglycerol activation of embryonic RasGRP3 is needed for the diabetes-associated vascular defects to manifest. Embryos that lacked RasGRP3 were protected from the damaging diabetic environment. Overt activation of RasGRP3 caused endothelial cells in culture to exhibit aberrant cell migration in response to endothelin-1. This faulty migration may be the cause of the defective vascular development, says the team. Importantly, they add, RasGRP3 presents itself as a possible target for protective therapy in diabetic pregnancies.

    Generation of New Cardiac Myocytes (p 1226)77

    Progenitor cell proliferation is the source of new myocytes in injured mammalian hearts, say Angert et al.

    It has been traditionally thought that after injury, the adult mammalian heart is unable to regenerate myocytes to adequately restore function. Instead, fibrotic scar tissue forms, and myocytes enlarge in an attempt to compensate for reduced contractility. The reduced functionality puts the heart under stress and, in many cases, leads to heart failure and death. Emerging evidence, however, challenges this dogma and indicates that adult cardiomyocytes can regenerate, albeit in small numbers; this has prompted speculation that if the process could be therapeutically promoted, repair could be improved. Angert et al decided to investigate the source of these new myocytes. They injured mouse hearts by infusing a chemical called isoproterenol for ten days and looked for regenerating cells using a marker (BrdU), which incorporates into DNA during cell replication. During and immediately after injury, about 20% of heart cell nuclei contained BrdU. Very few of these cells were myocytes, however. Most were cardiac progenitor cells. Later in recovery (one to four weeks), myocytes containing BrdU were apparent. The most straightforward explanation, say the authors, is that progenitors rapidly divide at the stage of injury and, later, differentiate into cardiomyocytes. Boosting progenitor proliferation might, therefore, be a method for improving adult heart regeneration.

    Pim-1 and Diabetic Cardiomyopathy (p 1238)78

    Promoting Pim-1 activity can protect against diabetic cardiomyopa-thy, report Katare et al.

    Cardiomyopathy, and subsequent heart failure, is all too common in patients with diabetes, but the mechanisms of pathology are not entirely understood. Katare et al postulated that a protein kinase called Pim-1 could be involved, because it is known to promote cardiomyocyte survival and to be down-regulated during diabetic cardio-myopathy. Here, the team showed that as cardiomyopathy progresses in diabetic mice, inhibitors of Pim-1 activity—namely, the phosphatase PP2A and the microRNA miR-1—in-creased in activity, concomitant with an increase in cardiomyocyte apoptosis. Importantly, inhibiting miR-1, or increasing expression of Pim-1, led to an increase in cardiomyocyte survival in vitro. In diabetic mice, systemic injection of Pim-1 attached to a heart-homing vector (AAV9) led to heart-specific expression of Pim-1. In turn, this improved cardiac function, prevented left ventricle dilation and heart failure, and improved survival of cardiac progenitor cells (progenitor cells had been shown previously to be exhausted in diabetic cardiomyopathic hearts). In conclusion, increasing Pim-1 activity in the heart could be a useful therapeutic approach for preventing heart failure in diabetes.

    Role of Tryptase in Abdominal Aortic Aneurysm (p 1316)79

    Zhang et al reveal tryptase as a mast cell mediator of aortic aneurysm.

    Abdominal aortic aneurysms (AAAs) that develop because of the expansion of the artery like a balloon can be life-threatening in the event of rupture. The hope is that AAAs can be caught early and surgically repaired. Zhang et al have now found that in patients with AAA, serum tryptase levels correlate with expansion and pose a risk for later surgical repair and mortality. This suggests that tryptase might serve as a useful biomarker for AAA development. The team also showed that high levels of serum tryptase were a result of an increase in mast cells, previously described in AAA patients and in mouse models of AAA. Furthermore, the increased tryptase was not just a reflection of AAA development, it was actually the cause. Mice lacking the gene for tryptase were protected from experimentally induced AAA lesion expansion, the team found. These mice had fewer inflammatory and apoptotic cells at AAA lesions and less elastin degradation. Importantly, methods used to block tryptase activity —such as protease inhibitors—might offer beneficial treatments for AAA patients, say the authors.

    CCICR and RhoA/ROCK in Vascular Smooth Muscle (p 1348)80

    Fernandez-Tenorio et al discover the wide-ranging cellular effects of a calcium channel in sustained vascular smooth muscle contraction.

    Sustained vascular smooth muscle contraction is associated with pathologies such as hypertension, angina, and cardiac arrhythmias. Although both L-type voltage-gated calcium channels (VGCCs) and contractile machinery sensitization by RhoA/Rho kinase have been implicated in sustained contraction, it is unclear how these elements are mechanistically interrelated. VGCCs both enable the influx of calcium from extracellular pools and control release of calcium from intracellular stores—namely, through the sarcoplasmic reticulum. The latter pathway is controlled via the activation of G protein/phospholipase C and other downstream cell signaling molecules. Fernandez-Tenorio et al showed that this so-called metabotropic pathway also activated the RhoA/Rho-mediated contractile machinery sensitization. These findings indicate that the effect of VGCCs on sustained vascular smooth muscle cell contraction encompasses more downstream pathways than previously thought. The results could be useful for optimizing treatments for hypertension, angina, and arrhythmias, say the team.

    HOXC9 and Endothelial Quiescence (p 1367)81

    HOXC9 halts vertebrate vascular development, report Stoll et al.

    Transcription factors of the homeo-box (HOX) family are important developmental morphogenes involved in the growth of numerous bodily structures and systems. Their role in vascular development, however, is not well understood. HOXC9 is expressed in blood vessels, which prompted Stoll et al to investigate whether this family member has any role in vascular development. They found that HOXC9 displayed a distinctive pattern of expression in cultured human vascular endothelial cells: sparsely growing cells had little of the factor, but expression increased along with cell density. Apparently, HOXC9 inhibited cell proliferation and the ability of the cells to migrate and form tubes in culture. Further experiments revealed that HOXC9 suppressed the expression of the interleukin (IL)-8 gene—a known angiogenic factor. Indeed, HOXC9’s effect on migration and tube formation could be reversed by administering exogenous IL-8. Proliferation remained unaltered, however, suggesting that HOXC9 targets another factor(s) to exert this effect. Using Ze-brafish embryos, the team showed that the overexpression of HOXC9, or indeed loss of IL-8, inhibited normal in vivo vascular development. Given that IL-8 can promote angiogenesis in certain tumors, boosting HOXC9 may be a good therapeutic countermeasure.

    PDGF Receptors and Epicardial EMT (p e15)82

    Smith et al have investigated the origins of cardiac fibroblasts and discovered that PDGFα receptor plays a crucial role.

    In the heart, the contractile cardio-myocytes may get most of the limelight, but they would be nothing without the supporting work of the endothelial cells, fibroblasts, and vascular smooth muscle cells (VSMCs). The latter two cell types are derived from a single source—epicardial cells of the early embryonic heart. In epicardial cells, two related receptors are expressed— PDGFα and β. Loss of PDGFβ results in the loss of VSMCs, which raises the obvious question—does loss of PDGFα result in loss of cardiac fibro-blasts? The answer is yes. Smith et al made mice that lacked PDGFα or β, or both, in epicardial cells. Whereas the lack of α or β led to loss of fibroblasts or VSMCs, respectvely, the loss of both led to a failure of epicardial cells to undergo epithelial-to-mesenchymal transition (EMT), an essential step before specific fates diverge. The authors also showed that the transcription factor Sox9 was downregulated in PDGF-lacking epicardium and that restoring Sox9 expression could restore EMT. Overproliferation of cardiac fibroblasts (cardiac fibrosis) is a major problem in long-term cardiac disease. Perhaps knowing how these cells form could offer new clues as to how to keep them under control.

    β3-ARs Mediate Exercise-Induced Cardioprotection (p 1448)83

    The cardioprotective effects of exercise have long been appreciated, and now Calvert et al have discovered how it works.

    A number of factors have been implicated in exercise-associated protection against ischemic injury in the heart, but so far, evidence has been largely circumstantial. For example, nitric oxide (NO)—a potent cardiac pro-tector—and its metabolites are increased in the blood during exercise, as are eNOS, the enzyme that drives NO synthesis, and stimulants of the β-adrenergic receptor (β-AR), which can activate eNOS. To understand the mechanics more fully, however, Cal-vert et al studied mice that lacked eNOS or β-AR. The mice were exercised for four weeks and then returned to a sedentary life for 24 hours, one week or four weeks before they were subjected to ischemia/reperfusion injury. Wild-type mice were protected from injury for at least a week after exercise cessation, whereas mice lacking eNOS or β-AR were not. The team also showed that exercise in wild-type mice increased NO metabolites in the heart itself, not just the blood, and this appeared to work through β-AR stimulation of eNOS. The findings not only reveal how exercise protects the heart, but also offer a number of possible targets for therapies aimed at protecting the heart from ischemia.

    Phosphatase-Resistant Gap Junctions (p 1459)84

    Keeping connexin 43 protein phos-phorylated and in its place can prevent arrhythmias, report Remo et al.

    Connexin 43 is one of the main proteins that form gap junctions— connections between heart cells that are essential for propagating impulses. Dysregulation of cell-to-cell coupling is thought to cause arrhythmias. Indeed, gap junction remodeling has been observed in a number of cardiac pathologies. To control the correct assembly, formation, and function of gap junctions, connexins are phosphorylated and dephosphory-lated by a cadre of regulated kinases and phosphatases. Connexin 43 itself has twelve known phosphorylation sites. Although much has been learned about these sites and their function, the findings have come largely from in vitro studies. To start to unravel in vivo physiology, Remo et al made mice whose connexin 43 was either resistant to phosphoryla-tion by a particular kinase, CK1δ,or permanently phosphorylated. The latter mice were protected from pathologic gap junction remodeling in response to stress (known to cause remodeling in wild-type mice) and to arrhythmias, whereas mice carrying the nonphosphorylatable form of connexin 43 were strongly susceptible to both. The authors, thus, suggest that modulation of connexin 43 phosphor-ylation may be a desirable approach for the treatment of arrhythmias.

    Circulation Research, vol 109, 2011

    Growth of Engineered Human Myocardium (p 47)85

    Stress and vessel cells are key ingredients when engineering human heart tissue, say Tulloch et al.

    Studies in model organisms show that mechanical stress is essential for correct cardiac development, as of course is vascularization. But Tulloch et al wanted to know how these factors affected human myocardial development. They grew human ES- and iPS-derived cardiomyocytes on 3D collagen matrices that were either fixed at both ends—providing a resistant structure for the cells to pull against when contracting—or loose at one end, providing no resistance. With resistance, the cardiomyocytes aligned themselves in the direction of the applied force, increased in size (hypertrophy) and increased their proliferation rate. Without resistance, they did not. Furthermore, adding vascular cells to the culture also increased cardiomyocyte proliferation. This occurred irrespective of the stress applied. Interestingly, the vascular cells self-organized into vessel-like structures in the collagen/cardiomyocyte tissue. When this tissue was engrafted onto rat hearts, the vessel structures appeared to transport blood after just one week. Such 3D matrix culturing of human ES- and IPS-derived cardiomy-ocytes not only offers insight into cardiac development, but may also be useful for developing therapeutic repair strategies, say the authors.

    Model of Canine Purkinje Cell Cycling (p 71)86

    Li and Rudy have built a mathematical model of a Purkinje cell to help understand the role of these cells in arrhythmogenic vulnerability.

    Purkinje fibers of the heart are specialized muscle fibers essential for rapidly conducting electrical impulses from the sinoatrial node (pacemaker) across the myocardium to coordinate chamber contractions. However, Pur-kinje fiber cells are also implicated in a number of cardiac arrhythmias. This is thought to be because Purkinje fiber cells are intrinsically more vulnerable to arrhythmic activity than regular cardio-myocytes. To understand this vulnerability, Li and Rudy incorporated data on canine Pukinje cell electrophysiology and intracellular calcium fluctuations into a mathematical Purkinje cell model. Importantly, they also included information on the type and subcellular distribution of ryanodine receptors— protein channels that control calcium release from intracellular stores. Such information had been omitted from previous Purkinje cell models but affected the timing and type of calcium fluctuations, and thus, action potentials, observed in the team’s new simulations. The new model should prove useful for developing an in-depth understanding of Purkinje cell electrical behavior and possibly for designing novel antiar-rhythmic approaches.

    Pannexin1 in the Regulation of Vasoconstriction (p 80)87

    Vessel cells coordinate contraction with the help of pannexin 1 protein, report Billaud et al.

    Vascular smooth muscle cells (VSMCs) must coordinate their contractile behavior to increase or decrease peripheral resistance to blood flow. A particular type of physical connection between cells—called a gap junction—is thought to be involved, but Billaud et al were not convinced that this was the entire story. They observed that VSMCs in a small mouse artery were not as tightly packed as those in the aorta. And, sure enough, the team could not detect gap junctions in these smaller arteries, while gap junctions were abundant in the aorta. The team did find pannexin 1, however. Pannexin proteins are membrane channels that are known to regulate cell-to-cell communications by release of purines and, thus, do not require cells to be in such close quarters. The team found that pannexin 1 regulated VSMC contraction mediated by α1-adrenergic receptors but not mediated by KCl stimulation. They also showed that pannexin 1 and the α1-adrenergic receptor physically interacted and colocalized at the VSMC membrane. This discovery of a novel communication mechanism controlling small artery VSMC contraction could have implications for the development of antihypertensive therapies.

    Atg7 Induces Autophagy (p 151)88

    Encouraging heart cells to clean up their trash could help prevent cardiomyopathies, suggest Pattison et al.

    Accumulation of cellular trash in the form of cytotoxic misfolded proteins is a characteristic of several cardiomyopathies. Under normal conditions, such protein trash is cleared from cells by, among other pathways, autophagy. During this process, membranous vesicles, called autophagosomes, form around protein and organelle debris and transfer it to the acidic lyso-somes for destruction. So far, only a handful of factors involved in au-tophagy have been identified. Pattison and colleagues focused specifically on one called Atg7 and investigated whether they could use it to boost autophagy in a rat cell model of desmin-related cardiomyopathy. Overexpression of Atg7, they showed, reduced the levels of protein aggregates in model cells and increased the amount of autophagic structures. Importantly, it also reduced cytotoxicity. Conversely, suppressing Atg7 expression by siRNA inhibited autophagy and exacerbated the myopathic phenotype of model cells. The next step, says the team, is to see whether Atg7 overexpression in vivo can also boost autophagy and thus slow, or even prevent, cardiomyopathies.

    MAFbx Mediates Cardiac Hypertrophy (p 161)89

    Curbing expression of MAFbx could protect hypertrophic hearts from progressing to heart failure, say Usui et al.

    The role of enzyme MAFbx is to tag specific proteins—by adding ubiquitin groups—and dispatch them to the proteasome for destruction. Because of the large degree of protein turnover that occurs in cardiac hypertrophy and remodeling, the ubiquitin-proteasome pathway, and MAFbx itself, have been implicated in this pathology. In a previous study, MAFbx overexpression was found to suppress hypertrophy. Complimentary MAFbx loss-of-function studies had never been done, however. Usui et al have now completed the picture by studying hypertrophy in mice lacking MAFbx. Surprisingly, they found that the loss of MAFbx inhibited hypertrophy and reduced cardiac dysfunction and remodeling. Further studies showed that levels of the transcription factor NF-KB and its gene targets were also reduced. MAFbx normally targets an NF-KB inhibitor for destruction, explain the authors. The previous study’s contrasting results suggest that overex-pressing MAFbx leads to the degradation of additional targets besides the NF-KB inhibitor and that this somehow suppresses hypertrophy. Whatever the reason, Usui et al say that suppressing endogenous MAFbx or NFKB could be a therapeutic strategy for preventing heart failure.

    AnkG: A Component of Intercellular Junctions (p 193)90

    AnkG is a molecular linchpin at heart cell boundaries, report Sato et al.

    Intercalated discs are the specialized cell-to-cell contacts between cardiac myocytes that enable synchronized contraction across the tissue. The contacts contain physical connections, such as desmosomes, gap junctions, and adherens junctions, as well as other communication complexes, such as sodium channels. These individual structures were traditionally considered to be separate entities, but accumulating evidence suggests that they might be interconnected. Sato et al add to that evidence by showing the sodium channel component and cytoskeletal adaptor, AnkG, is associated both with des-mosome protein, PKP2, and gap junction protein, Cx43. Loss of AnkG in cardiomyocytes altered the subcellular distribution of PKP2 and decreased the levels of Cx43, the team showed. Intercellular adhesion was also reduced, as was electrical coupling. Similarly, a loss of PKP2 decreased the abundance of AnkG and altered the distribution of sodium channels. Loss of gap junction components at intercalated discs has been implicated in arrhythmogenic right ventricular cardiomyopathy (ARVC). In light of these results, it appears that future studies of ARVC and other arrhythmias might be best approached by considering intercalated discs as singular complex units, suggest the team.

    AKAP150 in LQT8 (p 255)91

    Cheng et al propose a way to combat arrhythmias in Timothy syndrome.

    A mutation in the cytoplasmic loop of calcium channel protein, Cav1.2a, is known to cause Timothy syndrome, which is characterized by structural heart defects, arrhythmia, and autism spectrum disorders. The disease is also known as long QT syndrome 8, because it is associated with a prolonged depolarization-to-repolarization (QT) interval. It is not clear how the mutation causes channel dysfunction, but Cheng et al wondered if interaction with a cytoplasmic anchor protein called AKAP150 may be involved. They made transgenic mice that expressed the mutant channel and lacked AKAP150, and found these mice were protected from cardiac hypertophy and arrhythmia. In vitro analysis revealed that mutant channels functioned normally in the absence of AKAP150. The anchor appears to stabilize the mutant channels in the open configuration and might also promote clusters of mutant channels to open together - both of which would increase calcium influx and thus delay repolarization. In short, the removal of the perfectly normal AKAP150 protein fixed arrhythmias caused by the mutant Cav1.2a. When it comes to possible therapies, say the authors, disrupting the interaction between these two proteins might be sufficient.

    PGF Regulates Cardiac Adaptation (p 272)92

    Placental growth factor helps stressed hearts to adapt, report Accornero et al.

    Despite its name, placental growth factor (PGF) is found in many tissues, including the heart. PGF is elevated in human heart tissue and in cultured car-diomyocytes under low oxygen conditions. It is also elevated in the blood of patients after heart attack or during is-chemic cardiomyopathy. Accornero et al also wanted to know the role of PGF in such stress conditions. The team made mice that overexpressed PGF in cardiomyocytes, and compared the effect of heart stress in these mice with wild type mice and with mice that lacked PGF. When the hearts of these mice were subjected to pressure overload, the animals overexpressing PGF exhibited greater cardiac capillary growth, fibroblast proliferation and cardiomyocyte hypertrophy, and were protected from heart failure. On the other hand, mice that lacked PGF died of heart failure within a week. Even though the extra PGF was produced by cardiomyocytes, it was the capillary cells and fibroblasts that were directly affected, while cardiomyocyte hypertrophy was a secondary response. The protective effect of PGF may make it a useful therapeutic agent but the authors caution that trials with PGF’s close cousin VEGF for ischemic heart disease have yet to show promise.

    Antiangiogenic VEGF165bin Systemic Sclerosis (p e14)93

    Manetti et al suggest a way to boost blood vessel renewal in patients suffering from scleroderma.

    Scleroderma is a rare and devastating autoimmune disease that is characterized by widespread fibrosis and vascular damage. The chronic vessel damage causes tissue ischemia, which would normally lead to the production of proangiogenic factors. Paradoxically, scleroderma patients have high levels of a known proangiogenic factor, VEGF, but angiogenesis is still impaired. Manetti et al have recently worked out why. They found that scleroderma patients produce a variant of VEGF (VEGF165b) that is antiangiogenic. This variant, which is produced by alternative splicing, was discovered only recently, and previous studies of patient tissues had not differentiated between this variant and its proangiogenic form. A splicing factor called SRp55, known to drive production of VEGF165b, was also upregulated in these patients. And both SRp55 and VEGF165b were upregulated by TGF- β1. TGF-β1 is known to promote fibrosis in scleroderma patients. Thus, the new data suggests TGF- β1 drives the vascular damage as well. Lastly, the team showed that blocking VEGF165b could stimulate angiogenesis in patient-derived vascular cells, so the hope is that such an approach might also work in patients.

    Wnt Inhibitors in hESC Cardiogenesis (p 360)94

    Willems et al have identified a molecular booster of cardiomyocyte production.

    Given the relative scarcity of hearts available for transplant, researchers are looking for ways to repair injured or diseased hearts by replacing lost myo-cytes. Much hope is placed in stem cell strategies, but whether such cells come from within the body or from an external source - such as embryonic stem (ES) cells - improvements in the understanding and efficiency of cardiomyocyte differentiation are needed. Willems et al tested 550 small molecules individually on ES-derived mesoderm cells to see which, if any, would improve car-diomyocyte differentiation. They found just one - a molecule called IWR, which stands for inhibitor of the Wnt signaling response. Wnt is a secreted signal responsible for the differentiation and development of a variety of tissue types. When added to ES-derived mesoderm cells, IWR promoted the expression of cardiac-specific genes and converted up to 30% of cells into cardiomyocytes – a whopping 200-fold increase over controls. Other, better-known Wnt inhibitors also improved cardiomyocyte differentiation, the team showed. Since IWR boosts cardiomyocyte differentiation of ES cells, it will be interesting to see whether it can do the same for the heart’s own stem cells as well.

    Antibody Tagging for Imaging and Cell Delivery (p 365)95

    Ta et al have a new technique for delivering molecules and cells to specific body locations. Their first target: blood clots.

    The delivery of drugs, molecules, and therapeutic cells to particular body tissues, while often desired, is rarely easy. One strategy is to conjugate the molecule/cell of interest to an antibody that recognizes the target tissue. But such an approach often links the antibody to cargo in an array of conformations, some of which reduce antibody function. Ta et al have now developed a site-specific conjugation approach that creates just one antibody-cargo conformation, while maintaining antibody activity. To achieve this, the team used a bacterial enzyme that both recognizes and covalently links 2 peptide tag sequences. One tag was introduced into the antibody sequence – in this case an antibody that recognizes activated platelets. The other was added to the cargo -fluorescent proteins, magnetic particles, or cells. The fluorescence-conjugated antibodies bound activated platelets tightly in vitro, while in vivo the magnetic particle and cell-conjugated antibodies homed specifically to blood clots (which contain activated platelets). The new technique could be used to study, and potentially treat, thrombotic, atherosclerotic, and inflammatory diseases, say the team, but could also be adapted to target molecules or cells to any desired tissue.

    CD34+ Cell Therapy for Refactory Angina (p 428)96

    There is new hope for patients with refractory angina, say Losordo et al.

    Therapies for angina include lifestyle changes, such as weight loss and smoking cessation, medications such as anti-platelet drugs, beta-blockers, calcium channel blockers and nitrates, as well as surgical interventions. There are some patients, however - currently 850,000 in the U.S. - that have exhausted these options, and suffer from so-called refractory angina. Recent pre-clinical and early clinical data suggest that CD34+ cells might help. Although CD34+ cells are hematopoietic stem cells, they can also give rise to endothe-lial cells, secrete pro-angiogenic factors, and promote neovascularization in is-chemic heart tissue. Losordo et al now report data from a phase II double-blind trial in which 167 refractory angina patients had either their own CD34+ cells or placebo injected into their hearts. After six months, patients that received CD34+ cells had fewer episodes of angina and showed an increased tolerance to exercise compared with patients injected with placebo. Mortality was also lower. Interestingly, a lower dose of CD34+ cells (100,000) worked better than a higher dose (500,000). The researchers suggest that perhaps the high dose exceeds the optimum cell number for efficient paracrine effects. Whatever the case, the good news is that refractory angina patients could have access to another treatment option after all.

    Arginase 1 Is Regulated by LXRα (p 492)97

    Pourcet et al identify a new mechanism that promotes the regression of atherosclerotic plaques.

    Due to its slow life-long progression, the development of atherosclerotic plaques is difficult to control, even with optimal therapy. Therefore, attempts to promote the regression of preformed plaques are particularly attractive. Even though plaque regression is difficult to study, it has been reported that transplantation of atherosclerotic aorta from atherosclerosis-prone apoE-null mice to wild-type nonatherosclerotic mice results in plaque reduction. Using this ingenious model, Pourcet et al now show that plaque regression is accompanied by an increase in the expression of the anti-inflammatory enzyme arginase1 (Arg1). They report that that this increase is regulated by the liver X receptor alpha (LXRα) and that deletion of LXRα prevents the upregulation of Arg1 in regressive lesions. Nevertheless, LXRα did not directly bind to the Arg-1 gene; instead, it increased the expression of IRF8, which in concert with PU.1, stimulated Arg1 gene expression in macrophages. Although previous studies have shown that LXRs prevent inflammation, the work of Pourcet and colleagues reveals a new molecular pathway linking LXRs to plaque regression, raising the possibility that the pathway could be gainfully targeted to reduce inflammation in atherosclerotic lesions and to promote plaque regression.

    Orai1 and Neointima Formation (p 534)98

    Zhang et al find a new way to prevent abnormal smooth muscle cell growth.

    Although smooth muscle cells in normal blood vessels remain quiescent and contractile, disease or injury can cause these cells to change their phenotype and proliferate, thereby contributing to the formation of atherosclerotic lesions, hypertension, or restenosis after an-gioplasty. The processes that regulate smooth muscle cell proliferation are not fully understood; however, calcium signaling has been shown to play an essential role. Zhang et al report that Orail1, a protein involved in the generation of calcium release-activated calcium current, is required for the proliferation of smooth muscle cells in rat carotid arteries after balloon injury. They found that Orail1 levels were increased in proliferating smooth muscle cells of the injured artery and that knockdown of Orail1 decreased neointima formation. Because in cultured smooth muscle cells the knockdown of Orail prevented the nuclear translocation of the transcription factor NFAT, the authors suggest that calcium influx via Orail1 promotes cell growth by stimulating the nuclear translocation of NFAT and that Orail1 may be a new drug target for preventing abnormal smooth muscle cell growth.

    Cell Senescence in Pulmonary Hypertension (p 543)99

    Noureddine et al say that pulmonary hypertension may be due to accelerated aging of smooth muscle cells.

    Because chronic obstructive pulmonary disease (COPD) is usually diagnosed in the middle-aged or elderly, it has been long suspected to be a symptom of accelerated aging. Clarifying this relationship, Noureddine et al report that in pulmonary artery smooth muscle cells of COPD patients, the extent of telomere shortening, which is indicative of replicative senescence, is directly related to the severity of pulmonary hypertension. They found that the senescent cells were located near actively dividing cells, and, when the senescent cells were put in culture, they excreted factors that stimulated the growth of normal smooth muscle cells. Thus, not only do some cells in the lung age quickly, they also coax neighboring cells to grow. This causes thickening of the blood vessels and thereby an abnormal increase in blood pressure (pulmonary hypertension). Further understanding of the causes and consequences of pulmonary smooth muscle cell aging could lead to the development of new treatments for COPD, which, despite its status as the 4th leading cause of death in the United States, has no known cure.

    β-Myosin Heavy Chain in Smaller Myocytes (p 629)100

    A classic hypertrophy-associated protein might in fact be antihy-pertrophic, say Lopez et al.

    The β-myosin heavy chain protein (β-MyHC) is expressed in myocytes of the fetus, but after birth it is largely replaced by α-MyHC. During periods of cardiac hypertrophy, however, β-MyHC is once again activated. It was thought that this reactivation was part of the pathological process, but Lopez et al have now discovered that cardiac myocytes expressing β-MyHC do not undergo hypertrophy. The team analyzed between 10 000 and 20 000 cardiomyocytes from several hypertrophic mouse hearts and found that while in comparison with normal hearts, the number of cells expressing β-MyHC went up, these cells remained small. It was the cells that did not express β-MyHC that grew. All cells continued to express a-MyHC, so it appears to be the presence of β-MyHC rather than a switch from α-MyHC to /3-MyHC that prevented cell growth. The team also found that β-MyHC expressing cells tended to be located in particular regions of the heart, including the papillary muscle, perivascular regions, and the base of the junction between left and right ventricles. Additional characterization of these β-MyHC expressing cells might help reveal how they avoid hypertrophy, and could offer clues for future antihypertrophic therapies.

    SIRT1 Protects Endothelial Function (p 639)101

    Zhou et al suggest a possible means for improving vascular function and prolonging life.

    Mice that lack a signal transduction protein, p66Shc, are protected against atherosclerosis and diabetes-related vascular endothelial dysfunction. As a result, they enjoy a longer lifespan. Similarly, mice that over-express the chromatin remodeling protein SIRT1 also suffer less atherosclerosis and have better endothelial function. Zhou et al decided to see whether these 2 lifespan-controlling proteins somehow interact with one another. It turns out, they do. One clue was that in the aortas of diabetic mice, SIRT1 levels were decreased and p66Shc levels increased, while in the aortas of calorie-restricted mice – which have longer lifespans –SIRT1 was increased and p66Shc decreased. The team then showed that inhibition of SIRT1 in cultured vascular endothelial cells increased p66Shc expression. Conversely, over-expression of SIRT1, both in cultured cells and in vivo, decreased p66Shc expression. Finally the team confirmed that SIRT1 directly bound to the promoter region of the p66Shc gene and modified its chromatin to repress transcription. The authors suggest that this SIRT1-p66Shc interaction may be a novel therapeutic target for combating diabetes- and age-related cardiovascular disease.

    miR-15 Family and Cardiomyocyte Proliferation (p 670)102

    A microRNA called miR-195 puts a stop to heart cell division, report Porrello et al.

    Immediately following birth, myo-cytes of the mammalian heart stop dividing and become terminally differentiated. This exit from the cell cycle corresponds with a loss of the regenerative capacity of the heart. Porrello et al wondered whether microRNAs (miRs) might be involved in regulating this cell cycle arrest since miRs are known to regulate a wide range of developmental processes. The team found that 71 miRs were either up or down-regulated in neonatal mouse heart cells, of which miR-195 was the most highly upregulated. mIR-195 is a member of a family of miRs that are known to regulate the cell cycle in other tissues. Here, the team showed that miR-195 regulated the cycling of cardiac myocytes. They showed that knockdown of miR-195 in neonatal mice led to an increase in the number of mitotic heart cells, while premature expression of miR-195 interfered with normal heart development. miR-195 also suppressed the expression of a number of mRNAs involved in cell cycle progression. Understanding the precise mechanism of miR-195 and other regulators of cardiac myocyte cell cycle may be useful for therapeutically prompting adult cardiac myocytes to proliferate after heart injuries, say the team.

    Exosomes and Paracrine Effects of CD34+ Cells (p 724)103

    Exosomes are responsible for the angiogenic effects of CD34+ stem cells, report Losordo and colleagues.

    Although stem cell transplantation improves the function of injured hearts, the mechanism of their salubrious effects remains mysterious. Too few of these cells are incorporated into the injured tissue to account for the remarkable functional and physiological benefits that are observed. To account for this discrepancy, some investigators have suggested that stem cells secrete trophic factors that promote the growth of new blood vessels or new cells within the injured tissue (paracrine hypothesis). In an effort to explain the paracrine effect of stem cells, Losordo et al collected exosomes secreted by CD34+ stem cells, shown previously to reduce angina and lower the rates of amputation in patients with critical limb ischemia. They report that these exosomes were just as potent as the CD34+ cells in promoting the growth of endothelial cells in culture and in stimulating angiogenesis in vivo. Exosomes from non-CD34+ cells were ineffective. How stem cell-derived exosomes stimulate angiogenesis remains a mystery, but the authors suggest that the role of angiogenic microRNAs (miR-126 and miR-130), sequestered within these vesicles, is one mechanism to explore in future studies.

    Peroxiredoxin 2 Ameliorates Atherosclerosis (p 739)104

    Park et al uncover a unique role of peroxiredoxin 2 in preventing atherosclerotic lesion formation.

    Atherosclerotic lesions preferentially develop in areas where blood vessels are branched or curved. Turbulent blood flow in these areas stimulates the production of reactive oxygen species (ROS), which promote leukocyte adhesion to the vessel wall and stimulate the development of atherosclerotic plaques. Park et al show that vascular areas exposed to turbulent flow express high levels of the hydrogen peroxide-removing enzyme peroxiredoxin 2 (Prdx2) and that deletion of this enzyme increases vascular adhesion and the formation of atherosclerotic lesions in apoE-null mice. They report that loss of Prdx2 increases infiltration of immune cells into plaques and that the absence of this enzyme, either in vascular or immune cells, is equally atherogenic. Significantly, deletion of other peroxide-removing enzymes such as glutathione peroxidase and catalase was less harmful than Prdx2 deficiency, suggesting that Prdx-2 has a unique role in removing peroxides from sites at which they can cause the most damage. Such specificity of action may also explain the limited success of attempts to inhibit atherosclerosis by global antioxidant interventions.

    Redox Regulation of ATP Synthase (p 750)105

    Van Eyk and associates identify a mitochondrial redox sensor in failing hearts.

    Because of conduction defects, heart failure results in discoordinate contraction of the myocardium. Resyn-chronization of contraction by biven-tricular stimulation improves heart function and enhances long-term survival of patients with heart failure. Cardiac resynchronization therapy (CRT) also improves the energetic efficiency of the heart, but the molecular and cellular basis for this improvement remains unknown. In their previous work, Van Eyk et al had found that heart failure in dogs results in partial inhibition of mitochondrial ATP synthase and that this activity could be restored by CRT. They also found that CRT affects several mitochondrial proteins involved in energy production and redox regulation. They now link these two phenomena together, demonstrating that dys-synchronous heart failure results in the formation of disulfide bonds between the α- and the γ-subunits of ATP synthase as well as S-glutathiolation of the α-subunit. These changes were reversed by CRT, which induced S-nitrosation of the protein. The authors suggest that a uniquely reactive cysteine residue (Cys-294), located within the α-subunit of ATP synthase, functions as a redox switch that is able to sense the redox state and adjust energy production accordingly.

    Atheroprotective IgM-Secreting B1a Lymphocytes (p 830)106

    Boosting B1a cells could be one way to subdue atherosclerosis, say Kyaw et al.

    Although B lymphocytes collectively are known to put up a fight against atherosclerosis, the B2 lymphocytes, when transferred into atherosclerosis-prone mice, worsen the condition. Kyaw et al thus wondered which type of B cells were the do-gooders. Their prime suspect was B1a cells because depletion of these cells after splenec-tomy increases the risk for heart disease and atherosclerosis. Sure enough, transfer of B1a cells into splenectomized mice suffering from atherosclerosis improved their symptoms. In particular, the necrotic cores of atherosclerotic lesions were reduced in size and contained fewer dead cells. B1a cells are major producers of IgM antibodies and the team found that the level ofIgM in plasma and in atherosclerotic lesions was reduced after splenectomy and restored after B1a transfer. Furthermore, transfer of B1a cells that could not secrete IgM did not improve atherosclerosis symptoms in the splenectomized mice. Kyaw et al conclude that expanding the number of B1a cells while diminishing B2 lymphocytes may be an effective therapeutic strategy against atherosclerosis.

    Myocytes From LQTS 3-Specific iPS Cells (p 841)107

    Malan et al have made induced plu-ripotent stem (IPS) cells from a mouse model of human arrhythmia.

    Long QT syndrome (LQTS) is a disorder of the heart whereby cardio-myocytes are slow to repolarize and have prolonged action potentials, which can cause serious and sometimes fatal arrhythmias. A number of ion channel mutations have been identified to cause LQTS, but obtaining heart cells from patients to study the disease is not easy. Deriving iPS cells from patients’ fibro-blast cells and differentiating them to become cardiomyocytes offers an alternative source of cells for study. Such derivations have been achieved from patients with LQTS 1 and 2 mutations. Now Malan et al have derived iPS cells from mice carrying the human LQTS 3 mutation. In this proof-of-principle paper, the authors showed that LQTS 3 iPS cells could be differentiated into cardiomyocytes that displayed the hallmark electrophysiology of the disease. The next step will be to derive iPS cells from LQTS 3 patients. In the meantime, the mouse iPS cells provide a convenient resource for studying disease mechanisms and screening drugs, as well as reducing the need for animal experiments.

    miR-133 and Vascular Smooth Muscle Cells (p 880)108

    Torella et al have discovered a microRNA that can stop detrimental vessel cell division.

    MicroRNAs (miRs) are small non-coding RNA molecules that bind to and suppress expression of specific target mRNAs. As such, miRs are responsible for controlling an array of cellular processes. Torella et al were studying the process of phenotype switching—the switch from quiescence to proliferation and migration—in vascular smooth muscle cells (VSMCs) and wondered which miRs might be involved. They studied a pair of miRs, miR-1 and miR-133, which are expressed from the same gene (bicistronic) and are important in cardiac and skeletal muscle cells. Their function in VSMCs was hitherto unknown. The team showed that only miR-133 was expressed in VSMCs, whereas miR-1 expression was negligible. Expression of miR-133 dropped when VSMCs started to proliferate, and overexpression of miR-133 could prevent both proliferation and migration. MiR-133 targeted the mRNAs of the transcription factor Sp-1 and the actin-binding protein moesin, which promote proliferation and migration, respectively. VSMC proliferation is necessary for blood vessel repair but can be pathological if overgrowth occurs, such as in atherosclerosis and restenosis. The authors suggest that activating miR-133 in these instances could be clinically advantageous.

    Mechanisms of Constitutive IRAQI in AF (p 1031)109

    Makary et al suggest a scheme for stopping the perpetual progression of atrial fibrillation.

    Atrial fibrillation, the most common form of heart arrhythmia, is associated with fibrosis and remodeling of the atria, which in turn worsens the arrhythmia. This positive feedback loop is thought to be in part caused by the activation of an inward constitutive potassium current in the cardiomyocytes. In vitro evidence shows that this current can be diminished by the activation of protein kinase C, but, counter-intuitively, PKC is activated in patients with atrial fibrillation – where the current is clearly not curbed. Using a dog model of the disease, Makary et al have now discovered that different isoforms of PKC inhibit or activate the potassium current. PKCα, which inhibits the potassium current, was down-regulated in the dog model cells, while PKCε, which the team showed activated the current, was relocated to the plasma membrane. It is possible that this relocation would put PKCε in the perfect place to directly phosphorylate the relevant potassium channel. Whatever the target of PKCε might be, inhibiting the activity of PKCε while boosting that of PKCα might be a strategy for tackling atrial fibrillation, say the team.

    MSCs and Repair in Hibernating Myocardium (p 1044)110

    Injected stem cells induce resident cells to fix damaged hearts, say Suzuki et al.

    Clinical trials using mesenchymal stem cells (MSCs) to improve heart function are currently underway. These trials follow numerous reports that MSCs can improve cardiac function in animal models of heart disease and myocardial infarction. It is unclear how the MSCs work, however. Some reports suggest that MSCs differentiate into cardiomyocytes, others that MSCs have paracrine effects, possibly inducing resident cardiomyoctes or stem cells to give rise to new myocytes. Suzuki et al injected MSCs into the coronary arteries of pigs with hibernating myocardium - heart tissue suffering chronic ischemia and hypertrophy, but still viable - and found that cardiomyocyte numbers increased, cellular hypertrophy was reduced, and contractility improved. The new myocytes were not MSC-derived, but apparently resulted from the mobilization and differentiation of endogenous bone marrow progenitors and the proliferation of resident myocytes. The success in improving function in this animal model, which lacks infarction, suggests that early intervention with stem cell therapy, before infarction and scarring occur, could be beneficial in heart disease patients. This concept broadens the potential indications for cell therapy.

    Human Atrial AP Models (p 1055)111

    A new atrial myocyte model by Grandi et al is providing mechanistic insight into atrial fibrillation.

    Treatment and management of atrial fibrillation, the most common human heart arrhythmia, is hindered by a lack of mechanistic knowledge about the condition. It is hoped that computer simulations of atrial myocyte electro-physiology might provide clues as to why the pathology arises and then persists. However, none of the atrial myo-cyte simulations have, to date, included adequate details of calcium regulation -which recent evidence suggests goes awry in atrial fibrillation. Grandi et al have now developed a new atrial myo-cyte model based on the model for ventricle myocytes they had previously developed. Importantly the new model incorporates the crucial atrial myocyte calcium-handling data. Cytosolic calcium bursts (transients) are reportedly reduced in atrial myocytes during atrial fibrillation, and this is associated with reduced muscle contractility. Analysis of the data using this model suggests that blocking a potassium current specifically expressed in atrial myocytes can restore calcium transients. This potassium current might therefore be a good target for enhancing contractility in patients with atrial fibrillation, suggest the authors.

    MicroRNA-29 in Aortic Aneurysm Formation (p 1115)112

    Boon et al find that blocking a particular microRNA prevents aortic aneurysm.

    As we age, our blood vessels become weaker and more prone to aneu-rysms. Indeed, abdominal aortic aneu-rysm is a problem that affects approximately 9% of elderly men. Growth and development of normal blood vessel is regulated by, among other things, microRNAs (miRs), so Boon et al wondered whether miRs might also play a role in vessel aging and pathology. The team examined the aortas of old and young mice and found that 18 miRs were differentially expressed. However, only one of these, miR-29, controlled mRNA expression. miR-29 was upregulated not only in aging aortas, but also in mouse models of aortic aneurysm and in human aneurysm biopsies. miR-29 had previously been shown to repress the expression of extracellular matrix proteins in the heart after infarction, thereby reducing fibro-sis and scarring. These same ECM mR-NAs were the targets for miR-29 in aging aortas, but in this case the team showed that the result was vessel weakening. Inhibiting miR-29 prevented the downregulation of ECM proteins and, more importantly, the formation of an-eurysms in aged mice. Localized inhibition of miR-29 at the site of an aortic aneurysm might therefore be a way to aid repair, strengthen the vessel wall, and prevent future aneurysms.

    Hypoxia and Macrophage Lipid Content (p 1141)113

    Mice are good models for studying hypoxia in atherosclerosis, say Parathath et al.

    The cores of human atherosclerotic plaques are often far enough from the passing blood flow that they are deprived of an oxygen supply. This hypoxic environment is associated with the activation of a transcription factor called hypoxia inducible factor (HIF-1), which regulates genes involved in apoptosis, metabolism, inflammation, and other processes relevant to atherosclerosis. Whether hypoxia and HIF-1 are actually involved in atherogenesis, however, is not known. Mouse models of atherosclerosis were considered irrelevant for studying the role of hypoxia in atherogenesis because it was thought that due to the small size of mouse plaques oxygen could still reach the cores. Parathath et al now show that, in fact, mouse plaques do express HIF-1 as well as its transcriptional targets. The team also showed that mouse macro-phages had altered lipid metabolism under hypoxic conditions, with increased sterol content and decreased cholesterol efflux – changes that would likely worsen atherosclerosis. Blocking the activity of HIF-1 prevented these hypoxia effects, indicating the transcription factor was directly responsible. The findings of Parathath et al suggest that hypoxia has a negative impact on atherogenesis and that mice would be useful for studying the damaging effect of hypoxia and for finding ways to combat it.

    Linking Exercise Capacity With Mortality (p 1162)114

    A genetic proclivity for exercise is linked to longevity, report Koch et al.

    That exercise decreases the risk for cardiovascular disease is well-known, but Koch et al now show that you can be born with this benefit. Well, at least rats can. The researchers selectively bred rats over 14 or so generations until they had populations of low capacity runners (LCRs) and high capacity runners (HCRs), as determined by treadmill testing. Then, they compared oxygen uptake, myocardial function, endurance performance, and body mass in adult and aged rats from the 2 groups. As the rats progressed from adulthood to old age, the HCRs had sustained activity levels, energy expenditure, and lean body mass. They also had lower blood pressure, improved cardiomy-ocyte function – assessed by contractility, morphology and intracellular calcium handling – and longer lifespans. The finding that longevity is linked with a genetic propensity for exercise does not mean that those of us who are naturally less active will not reap the same benefits from exercise. Rather, the research suggests that the LCR and HCR model rats will be excellent tools for studying the biological pathways that link aerobic activity with healthy aging and longevity – work likely to benefit everybody.

    CD40L-Mac-1 and Atherosclerosis (p 1269)115

    Wolfet al have devised a safer way to block CD40L in atherosclerosis.

    CD40L is a cell surface glycoprotein that is expressed on a variety of cell types and that interacts with several cell surface receptors. One of its main roles is to regulate lymphocyte function, and therefore, it is involved in a number of inflammatory diseases, including atherosclerosis. Blocking the action of CD40L reduces the formation and growth of atherosclerotic plaques and lowers their lipid and monocyte content. Despite these beneficial effects, clinical trials with anti-CD40L have identified some dangerous side effects, such as the risk of thromboembolism and impaired host immunity. Wolf et al have now designed a specific peptide that blocks the interaction of CD40L with the receptor Mac-1, which is found on leukocytes, but that leaves interactions with other receptors intact. Blocking this interaction in a mouse model of atherosclerosis reduced leukocyte recruitment to plaques and attenuated plaque growth. Importantly, the peptide did not affect thrombus formation -thought to be mediated via the interaction of CD40L with a platelet receptor -nor did it alter the basic immunological characteristics of these mice. The investigators suggest that targeted disruption of the CD40L-Mac-1 interaction may be a better strategy for treating atherosclerosis than the general inhibition of CD40L.

    Epigenetic Control of Endothelial Lineage (p 1219)116

    Endothelial progenitor cells require epigenetic remodeling to switch on endothelial genes, say Ohtani et al.

    Endothelial progenitors are necessary for vascular repair and neo-vascularization after ischemia, but little is known about the mechanisms controlling the differentiation of these progenitor cells into functional endothelial cells. Ohtani et al found that in endothelial progenitors the promoter regions of a number of endothelial-specific genes were tagged with epigenetic marks of silencing – DNA and histone methyl-ation. However, when the endothelial progenitor cells were exposed to hypoxic conditions, these marks of silencing were removed and replaced with marks of active chromatin - histone acetylation. Hypoxic tissue is known to be a fertile ground for recruiting endothelial progenitors for neovascularization. The team found that pharmacological inhibition of the enzymes that methylate histones and that remove histone acetyl groups could activate the endothelium-specific gene, eNOS. Endothelial progenitor cells, particularly those expressing eNOS, have been shown to improve functional recovery after ischemia in animal models. Understanding how endothelial progenitor cells differentiate and switch on their essential genes could thus help in improving clinical approaches to ischemic injury repair.

    Spontaneous Termination of Human VF (p 1309)117

    Blocking potassium channels in diseased hearts could avert potentially fatal fibrillations, report Farid et al.

    Ventricular fibrillation – the rapid uncoordinated contraction of ventricle muscle – is the most common cause of sudden cardiac death in humans. Often, the only way to stop ventricular fibrillation is with an electric shock. Consequently, patients with severe cardiomy-opathy who are at risk of ventricular fibrillation are generally treated using implantable defibrillator devices, which deliver tiny electric jolts to the heart when arrhythmias are detected. Farid et al have now found evidence to suggest that an alternative or adjunctive therapy might be possible. Myopathic human hearts showed increased expression of ATP-dependent potassium channels in their left ventricular endocardiums compared with those of normal hearts. This aberrant expression was thought to be the cause of the electrical instability. Importantly, blocking potassium channel activity with a drug called glibenclamide could induce spontaneous termination of ventricular fibrillation. In addition to use in cardiomyopathy patients K-ATP channel blockade by glibenclamide might prove useful in patients that need defibrillation after cardiac surgery or those that require cardiopulmonary resuscitation, say the authors.

    Plakoglobin and Adipogenesis in ARVC (p 1342)118

    Too much plakoglobin protein in the nuclei of heart cells turns them into fat cells and causes arrhythmia, report Lombardi et al.

    Arrhythmogenic right ventricular cardiomyopathy (ARVC) is most commonly caused by mutations to genes encoding desmosome proteins, such as plakoglobin (PG). ARVC-causing mutations in PG are known to release the protein from intercellular junctions and drive its accumulation in the nucleus where it suppresses canonical Wnt signaling. To determine whether nuclear accumulation was essential for the pathogenesis of ARVC, Lombardi and colleagues made transgenic mice that overexpressed mutant or wild-type PG in the heart. They found that both proteins accumulated in the nucleus (exclusively, in the case of mutant PG), that the mice suffered arrhythmias, and that their hearts contained large numbers of fat cells (adipocytes)—a characteristic feature of ARVC. Indeed, cardiac progenitor cells isolated from the mice could spontaneously develop into adipocytes in culture. These cells also showed suppression of Wnt signaling. Treating the cells with a drug called BIO restored Wnt signaling and reversed the proadipogenic phenotype. Although the results might not be applicable to other causes of ARVC, they do suggest that those cases caused by mutant PG might benefit from a heart-directed reactivation of canonical Wnt signaling.

    Wnt Signaling Regulates CSP Cells (p 1363)119

    Wnt signaling inhibits cardiac progenitor cell proliferation and reduces the ability of heart to repair, say Oikonomopoulos et al.

    Progenitor cells in the adult heart are activated after injury and help to regenerate the tissue. Little is known about the mechanisms that regulate progenitor cell renewal, however. Oikono-mopoulos and colleagues wondered whether the signaling protein Wnt might be involved, because it has been shown that Wnt promotes the proliferation of neonatal and embryonic cardiac progenitors in vitro and in vivo. Wnt can affect the development and differentiation of tissues in different ways, depending on the type of tissue and the stage of development. For example, early in embryo development, Wnt activates cardiac differentiation, but later, it becomes inhibitory. Sure enough, the team found that unlike in embryonic and neonatal progenitors, Wnt signaling in adult progenitors inhibited proliferation—both in the culture dish and when injected into mouse hearts. Wnt signaling led to a 40-fold increase in expression of the growth factor binding protein, IGFBP3, and in the absence of Wnt signals, overexpression of IGFBP3 could mimic the effect of Wnt signaling. The authors say that inhibiting Wnt or IGFBP3 might, therefore, be an effective approach for improving tissue regeneration after cardiac injury.

    Plasmacytoid Dendritic Cells and Atherosclerosis (p 1387)120

    Plasmacytoid dendritic cells keep atherosclerotic inflammation in check, report Daissormont et al.

    Plasmacytoid dendritic cells (PDCs) make up a tiny percentage of total leukocytes and are a small but consistent presence in atherosclerotic plaques. In vitro studies suggest that PDCs might contribute to the pathogenesis of atherosclerosis, particularly to the desta-bilization of plaques—a dangerous precursor to blood vessel occlusion. However, their role in atherosclerosis in vivo has not been established. Until now, that is. Daissormont et al depleted PDCs in a mouse model of atherosclerosis and showed that plaque volumes increased and that they contained greater numbers of T cells. The number of T cells was also increased in the blood and spleen. Together, these data suggested that PDCs suppress T-cell proliferation—which the team confirmed in vitro—and that this suppression occurred throughout the body, not only in plaques. PDCs isolated from atherosclerotic mice expressed higher levels of the im-munomodulatory factor IDO. Furthermore, in cocultures of PDCs and T cells, IDO inhibition increased the proliferation of T cells, showing that PDC suppression of T-cell proliferation is IDO dependent. This suggests that boosting PDC/IDO activity might be a new therapeutic strategy in the fight against atherosclerosis.

    Footnotes

    Circulation Research “In This Issue” Anthology: In the May 14, 2010 issue, we inaugurated a new feature, the In This Issue page, which highlights articles that the editors feel are particularly important by providing a short synopsis written in a language that can be understood by the non-specialist. Our purpose in creating this new feature was two-fold: first, to call the attention of readers to important articles and, second, to enable all readers to grasp, easily and quickly, the significance of these papers. We believe that this initiative has been successful and, as a further service to our readers, provide below a compendium of these pages from 2010 & 2011, with a promise to publish yearly anthologies going forward. Each summary is accompanied by the corresponding citation, so that readers can easily find the entire article should they wish to read it. This remarkable anthology of outstanding articles attests to the diversity and depth of the work published in Circulation Research. — The Editors

    Correspondence to

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