doi: 10.1161/01.RES.0000130526.20854.fa
© 2004 American Heart Association, Inc.
Reviews |
Inflammatory Cytokines and Postmyocardial Infarction Remodeling
From Heart & Stroke/Richard Lewar Centre of Excellence, University of Toronto; and Division of Cardiology, Toronto General Hospital, University Health Network, Toronto, Canada.
Correspondence to Dr. Peter Liu, Heart & Stroke/RL Centre of Excellence, NCSB11-1266, Toronto General Hospital, 200 Elizabeth Street, Toronto, Ontario, M5G 2C4, Canada. E-mail peter.liu{at}utoronto.ca
This Review is part of a thematic series on Chemokines and Cytokines, which includes the following articles:
Inflammatory Mediators and the Failing Heart: Past, Present and the Foreseeable Future
Inflammatory Cytokines and Postmyocardial Infarction Remodeling
Cytokines in Ventricular Function
Chemokines/Cytokines
Peter Liu Guest Editor
 |
Abstract |
|---|
 Top Abstract IntroductionTriggers of Cytokine Production...Cytokines and Acute Myocardial...Chronic Remodeling...Clinical Implications: Cytokines...References |
|---|
Inflammatory response and cytokine elaboration are particularly active after myocardial infarction and contribute to cardiac remodeling and eventual host outcome. The triggers of cytokine release in the acute postinfarction period include mechanical deformation, ischemic stimulus, reactive oxygen species (ROS), and cytokine self-amplification pathways. Acutely, the elaboration of tumor necrosis factor, IL-1 and IL-6, transforming growth factor families of cytokines, contribute to survival or deaths of myocytes, modulation of cardiac contractility, alterations of vascular endothelium, and recruitment of additional circulating cells of inflammation to the injured myocardium. This leads to further local oxidative stress and remodeling but also initiates the processes of wound healing. Chronically, sustained presence of cytokines leads to myocyte phenotype transition and activation of matrix metalloproteinases that modifies interstitial matrix, augmenting further the remodeling process. This in turn alters the local collagen composition and also the integrins that constitute the interface between myocytes and the matrix. These processes ultimately, when favorable, pave the way for angiogenesis and cellular regeneration. Thus, the insightful modulation of cytokines through current and future therapies could promote improved healing and cardiac remodeling postmyocardial infarction.
Key Words: remodeling • cytokines • inflammation • myocardial infarction • matrix • integrins
|
Introduction |
|---|
|
TopAbstractIntroductionTriggers of Cytokine Production...Cytokines and Acute Myocardial...Chronic Remodeling...Clinical Implications: Cytokines...References |
|---|
Inflammatory response and cytokine elaboration are integral components of the host response to tissue injury and plays a particularly active role after myocardial infarction. The degree of the inflammatory response in turn is an important determinant of the host’s outcome. Cytokines are released by the host myocardium to modulate tissue repair and adaptation after injury.
Cytokines such as tumor necrosis factor-alpha (TNF-
) or interleukin-6 (IL-6) are elaborated soon after myocardial ischemic injury and can acutely regulate myocyte survival or apoptosis and trigger additional cellular inflammatory response. Chronically, cytokines can mediate repair and remodeling through activating matrix metalloproteinases and collagen formation, and regulate integrins and angiogenesis and progenitor cell mobilization.
The consequences of inflammatory cytokine effects can be favorable, leading to healing and restoration of function, or unfavorable, leading to acute cardiac rupture or chronic dilatation, paving way for heart failure. The critical importance of the cardiac remodeling process postmyocardial infarction in the survival of the patient is well-documented from several postmyocardial infarction follow-up studies. Excessive ventricular dilatation readily leads to increased mortality.1
This review focuses on some of these recent developments and evolving concepts of cytokine activation postmyocardial infarction.
|
Triggers of Cytokine Production Postmyocardial Infarction |
|---|
|
TopAbstractIntroductionTriggers of Cytokine Production...Cytokines and Acute Myocardial...Chronic Remodeling...Clinical Implications: Cytokines...References |
|---|
Proinflammatory cytokines, such as TNF-
, IL-1ß, and IL-6, are not constitutively expressed in the normal heart.2,3 Upregulation and production of these cytokines represent an intrinsic or an innate stress response against myocardial injury.4 In rodent models of myocardial infarction, within the first hours to 1 day, there are robust upregulations of intramyocardial cytokines including TNF-, IL-1ß, and IL-6 mRNA expression in the infarct area (up to 50-fold), as well as in the noninfarcted myocardium (up to 15-fold).5,6 This robust upregulation may return to baseline levels if the infarction is small. However, if the infarction is large, or if host inflammatory response is exuberant, there can be either sustained cytokine upregulation or a second wave of cytokine upregulation, corresponding to chronic remodeling phase. The second wave can also extend to involve the noninfarct remote zone, mediating important remodeling process in the entire myocardium.6,7 The elevation in cytokine expression precedes the consequent increase in local matrix metalloproteinase (MMP) activity (eg, MMP-2 and 9) in the infarct area, as well as the increase in natriuretic peptides (ANP and BNP) and collagen expression in the noninfarcted myocardium.5
Mechanical Stress Triggers Cytokine Production
Cytokines such as TNF- and IL-6 are rapidly released in the central ischemic zone during infarction but are usually maximal in the border zone.6,8 Ischemic stress represents a potent trigger for cytokine production, but direct myocardial mechanical stretch—maximal in the infarct and peri-infarct zone—is also a potent regulator (Figure 1). Kapadia et al have shown that direct hemodynamic stretch can trigger myocardial production of TNF- de novo within 30 minutes.2 Mechanical stress associated with myocardial infarction leads to the prompt production of TNF- and IL-6 in the myocardium. Mechanical stimulus acts through potential mechanosensors (integrins, cytoskeleton, and sarcolemmal proteins) and converts into 3 major intracellular cross-talking signal transduction pathways, mitogen-activated protein kinase (MAPK), JAK-signal transducer and activator of transcription (STAT), and calcineurin-dependent pathways. These pathways activate cognate downstream nuclear transcription factors, such as NF-
B and AP-1, which are required for the induction of most cytokine genes, including TNF- and IL-6.9
|
Intrinsic Response to External Stress, Including Ischemia
The robust upregulation of cytokines after ischemia also directly coincides with the transient induction of stress-induced transcription factors such as C/AATT-enhancer binding protein (C/EBP)-ß and STAT3 phosphorylation.5 This is also associated with local gp130 and IL-6 induction, again part of the host stress response signaling system, which can lead to phenotype transition, such as induction of hypertrophy.10,11 These signaling pathways that ultimately lead to cytokine induction are integrators of cellular stress signals and are upregulated in response to diverse stimuli such as hypoxia, free radical excess, osmotic dysregulation, and early membrane injury.
Other novel stress-induced inflammatory regulators, such as peroxisome proliferator-activated receptor (PPAR-
), may also play a role in ischemic inflammation. PPARs have been implicated as regulators of cellular proliferation and host inflammatory response. In a murine postinfarction model, PPAR agonist pioglitazone was found to improve function and remodeling, and was associated with significant reductions in inflammatory cytokine levels in the myocardium.12 Rosiglitazone, another PPAR- agonist, can also reverse the upregulation of CD11b/CD18 and downregulation of cytokines in ischemia-reperfusion models.13
Reactive Oxygen Species as Activators
Recent studies suggest that cytokines not only induce reactive oxygen species (ROS) production but also are themselves induced by ROS.14,15 In this regard, H2O2 can directly induce myocardial TNF production via the p38 MAPK pathway and, in turn, mediate myocardial dysfunction and apoptosis.14
In a canine model of myocardial ischemia reperfusion, Kukielka et al have noted that cardiac IL-6 induction was minimal during 4 hours of ischemia but was markedly enhanced during 1 hour of ischemia followed by 3 hours of reperfusion, despite similar degrees of injury and blood flow reductions.16 The authors originally postulated that neutrophil infiltration was responsible for the difference. However, more recent information linking the induction of NF-B and AP-1 to the intermediate and nonlethal levels of reactive oxygen radicals may be an exciting alternate hypothesis, because the latter are present in large quantities during reperfusion.17
ROS during myocardial ischemia or reperfusion may originate from the mitochondria, xanthine oxidase, and the phagocytic nicotinamide adenine dinucleotide phosphate oxidase. ROS can participate as second messengers in host myocardial signaling events, including MAP kinases, small GTP-binding proteins, the Src family of tyrosine kinases, and cytokines cascades, activating stress-related nuclear transcription factors, leading to cellular hypertrophy and apoptosis.18,19
Cytokine Amplification Pathways
Cytokines also have the unique ability to self-amplify through a positive feedback loop targeting the transcription factor NF-B. For example, the upregulation of cytokines such as TNF- in a localized area of the myocardium, eg, ischemic region, can easily induce TNF- upregulation in neighboring normal myocardium, leading to amplified cytokine effects. Irwin et al from our group demonstrated that TNF- mRNA was maximally detectable acutely in the infarct and peri-infarct zones during the first days postmyocardial infarction. In contrast, by day 35 late postmyocardial infarction, the "contralateral normal zone" in the infarcted hearts showed the highest level of TNF- expression.6
To definitively demonstrate that cytokines such as TNF- can upregulate remote regions in the heart through a "virtual" network, we have recently used a novel heterotopic cardiac transplant model, in which myocardial infarction was imposed on the heart in the abdomen, whereas the native recipient heart, totally undisturbed by surgery, is observed during subsequent days of follow-up.20 Most surprisingly, the otherwise uninfarcted and undisturbed recipient heart demonstrated a significant decrease in LV fractional shortening and increase in LV end-diastolic dimension after infarction in the abdominal heart. This was accompanied by increased TNF- levels also in the recipient heart. This set of unusual observations was completely abolished by the intravenous administration of a TNF- antagonist, Etanercept. This suggests that cytokines such as TNF can activate a remote amplification network that mediates potent remodeling effect not only in areas of acute injury but also in remote regions currently still surviving to recruit additional tissue for global repair and remodeling process.
Additional inflammatory cytokine amplification takes place through direct recruitment of inflammatory cells to the site of injury. Early after myocardial ischemia, adhesive cytokines such as monocyte chemoattractant protein, a potent mononuclear cell chemoattractant, is also induced in the myocardium.21 This promotes transmigration of macrophages from the blood and, in turn, provides an additional source of local cytokine production and amplification of the local inflammatory response.22
Although mononuclear cells such as macrophages and neutrophils play a well-documented prominent role in early inflammation, other inflammatory cells also play important roles. Mast cell, a bone marrow-derived inflammatory cell with prepackaged inflammatory cytokines and growth factors, also accumulates in the ischemic-reperfused myocardium by 3 days postmyocardial infarction. Stem cell factor, secreted by a subset of macrophages in the reperfused area, may be an important factor for mast cell mobilization.23 In the early stage of injury, mast cell participates in the release of additional preformed TNF, which can further attract mononuclear cells to the injured tissue.
|
Cytokines and Acute Myocardial Remodeling Postinfarction |
|---|
|
TopAbstractIntroductionTriggers of Cytokine Production...Cytokines and Acute Myocardial...Chronic Remodeling...Clinical Implications: Cytokines...References |
|---|
The stimulation of cytokine secretion in response to myocardial ischemia or infarction has profound effects on myocardium that provokes at least 4 changes directly in cardiac myocytes that contribute to the phenotype reprogramming or remodeling: progressive myocyte apoptosis,24,25 myocyte hypertrophy,26 defects in contractility,27 and inflammatory signal transduction.28 Chronically, cytokines have additional effects on extracellular matrix, integrins, and vascular and cardiac regeneration. Among the cytokines, TNF-
, IL-1ß, and IL-66,7 are most commonly associated with the remodeling process postmyocardial infarction.
Paradoxical Effect of Cytokines on Myocyte Survival and Apoptosis
Cytokines such as TNF appear to have a significant pleiotropic effect on the host cells, with the potential for apoptosis versus cellular preservation and hypertrophy. The net balance between these 2 opposing processes defines the net cellular remodeling (Figure 1).
TNF ligand achieves all its different physiological and pathological effects by binding to 2 distinct surface receptors; TNF receptor 1 (TNF-R1) and TNF receptor 2 (TNF-R2),29,30 TNF-R1 and TNF-R2 share a conserved extracellular domain with both containing 4 tandemly repeated cysteine-rich motifs.29
TNF-R1 belongs to cell surface "death receptors" family, a growing subset of TNF-R superfamily that also includes Fas/CD95,31,32 death receptor 3 (DR3),33 DR4,34 DR5,35 and DR6.36 All death receptors contain a signature cytoplasmic death domain, a region of 
80 amino acids in length toward the carboxyl-terminus of the receptor.37 In response to TNF, TNF-R1 is trimerized, and death domain-containing molecule TNF receptor–associated death domain protein (TRADD) is recruited to the cytoplasmic regions of the receptors through homotypic death domain interactions.38 TNF receptor–associated death domain protein recruits the downstream signaling adaptor molecules Fas-associated death domain. Fas-associated death domain interacts with procaspase 8, thereby stimulating caspase-8 autoproteolytic activation and, in turn, initiate cell death by destroying cell’s own repair mechanisms. However, activation of the Bcl-2 family of proteins, such as Bcl-2, Bcl-x, may alter the release of cytochrome C and the net final balances of these signals will determine whether apoptosis will proceed to completion.
Beside the caspase-dependent apoptotic pathway, TNF has also been shown to induce cell death through the recruitment of a protein termed FAN (factor associated with neutral sphingomyelinase).39 FAN then interacts directly with membrane-bound neutral sphingomyelinase with resultant generation of ceramide.40 Ceramide triggers apoptosis via a mechanism postulated to involve ROS.41
Conversely, the cytoprotective effect of TNF- may converge through the activation of the transcription factors NF-B and stress-activated protein kinase/c-Jun N-terminal kinase (JNK), leading to the activation of cytoprotective gene expression. Tumor necrosis factor receptor–associated factors, such as TRAF2, interact with and activate downstream signaling molecules such as NF-B–inducing kinase, a member of the serine/threonine MAPK kinase (MEK) kinase (MEKK) family.42,43 NF-B–inducing kinase phosphorylates IKK (inhibitor of B kinase) leads to NF-B translocation to the nucleus and activation of genes involved in cellular inflammation, growth, and survival.44,45 Several other molecules, such as RIP, protein kinase B (PKB or AKT), apoptosis-stimulating kinase (ASK1), and germinal center kinase (GCK), also facilitate the TNF-induced stimulation of either NF-B or stress-activated protein kinase/JNK activities to promote cell preservation and survival.46,47
The cardioprotective action of TNF- is best illustrated in mice with combined genetic ablation of the TNF-R1 and TNF-R2 receptors. TNF-R1 and TNF-R2 double-receptor knockout mice undergoing left coronary ligation had significantly larger infarct size and increased myocyte apoptosis when compared with normal control mice. The hypertrophic effect of TNF- was demonstrated in several independent studies. Physiologically relevant concentrations of TNF- provoke a hypertrophic response by increasing the synthesis of structural and contractile protein in adult feline cardiac myocyte.26 Moreover, transgenic mice with cardiac-specific overexpessing TNF-–developed cardiac hypertrophy.48
Similar finding have been observed for the so-called IL-6 family of cytokines that include IL-6, leukemia inhibitory factor, oncostatin M, ciliary neurotrophic factor, IL-11, and cardiotrophin-1. The effects of this family of cytokines on multiple cell types, including myocytes, are achieved through gp130, a signal-transducing subunit shared by the receptors for the IL-6 family of cytokines. Dimerization of gp130 on IL-6–binding to its receptor leads to the activation of JAK and phosphorylation of gp130.10 These events lead to the activation of multiple signal transduction pathways, including the most prominent signal transducer and activator of transcription, Ras-MAPK, and phosphatidylinositol-3 kinase pathways49 that result in cytoprotective response in the heart. The significant role for IL-6 in tissue repair was demonstrated by experiments in which IL-6–/– knockout mice have significantly delayed cutaneous wound healing and worse outcome.50
Other cytokines are also potentially protective in the setting of myocardial infarction, including the bone marrow-derived cytokines such as granulocyte colony-stimulating factor (G-CSF) and erythropoietin (EPO). In addition to their potential role of expanding and mobilizing bone marrow-derived progenitor cells, they may have direct myocardial-protective effects. G-CSF has been found to directly improve ventricular remodeling and function.51 EPO, important for erythrocyte survival and differentiation, has the ability to maintain vascular autoregulation and attenuating primary (apoptotic) and secondary (inflammatory) causes of cell death. In a rat model of infarction, EPO reduces cardiac myocyte loss by 50%, sufficient to normalize hemodynamic function after reperfusion.52
Cytokines in Altering Cardiac Contractility
Cytokines are capable of decreasing left ventricle performance and myocyte contractility directly and indirectly. In the setting of injury, the reduction in contractility mediated by TNF and IL-6 may be an adaptive response to decrease myocardial energy demand. TNF- and IL-6 can attenuate myocyte contractility directly through the immediate reduction of systolic cytosolic [Ca2+] via alterations in sarcoplasmic reticulum function, reversible by the removal of the cytokine exposure.53 However, TNF- is also capable of decreasing myocyte contractility indirectly through nitric oxide-dependent attenuation of myofilament Ca2+ sensitivity.54
Alternatively, TNF provokes negative inotropic effects in myocytes partially through the neutral sphingomyelinase pathway. Early, within minutes after cardiac injury, TNF decreases systolic function by altering calcium-induced calcium release by the sarcoplasmic reticulum and by disrupting the l-type calcium channel.55 In this phase, the binding of TNF to TNF-R1 leads to the release of sphingolipid metabolite (stress-induced second messenger) via sphingomyelin degeneration. Oral et al also reported that sphingosine production correlated directly with calcium imbalance.56 Furthermore, blockade of sphingosine production negatively regulated TNF-–induced contractile dysfunction. However, late (days) after MI, there is iNOS induction leading to increased production of nitric oxide, which further amplifies myofilament desensitization to calcium, resulting in sustained contractile abnormality. Furthermore, it has been shown that sustained expression of TNF can also lead to decreased SERCA2A expression, which is essential for the re-uptake of calcium in an energy-dependent manner after excitation–contraction of the cardiac myocyte.
Effects on Inflammatory Cell Infiltrate Through the Vasculature
Cytokines such as TNF and IL-1 and IL-6 are expressed at high levels in the vasculature in the ischemic myocardium. However, the upregulation of cytokines may alter the endothelial phenotype and set the stage toward an angiogenic program. Specifically, the presence of angiogenic factors, such as VEGF, HIF-, and iNOS, both in animal models and human models after myocardial infarction, enhances the process of healing and angiogenesis.57–59
In the setting of ischemia reperfusion, infiltration of neutrophils represents an important step in the local amplification of the initial inflammatory response triggered by the cytokines. Neutrophil migration depends on their interaction with the endothelial cells via L-selectin (originates from hematopoietic cells) and P-selectin (constitutively present in endothelial cells and platelets).60 The leukocyte ß-integrins are, in turn, involved in adhesion to endothelial cells, particularly the ß2 integrins (CD18), lymphocyte function antigen-1 (CD11a/CD18), macrophage antigen-1 (CD11b/CD18), or the very late antigen-4 (CD49d/CD29). Once inflammatory cell transmigration takes place, further cytokines are released to facilitate extravasation into the extravascular tissue. Recent data suggest that myosin light chain kinase-mediated myosin light chain phosphorylation is important in loosening the gap between endothelial cells and thereby increasing the vessel wall permeability for these cells.61
Insight into the role of neutrophil infiltration in ischemic reperfusion has been gained mainly through loss of function studies. Ischemia reperfusion interventions in CD18–/– and ICAM-1–/– knockout murine models both resulted in decrease in infarct size and neutrophil infiltration, when compared with wild-type controls. This process has been similarly targeted in clinical trials involving the administration of monoclonal antibody against CD18. However, the result to date has been disappointing. A possible explanation is that leukocytes are secondary mediators of inflammation, and targeting the cause of inflammation is ultimately the more efficacious strategy.
Oxidative Stress Signaling
Cytokines and neutrophils collaborate to play an important role in ischemia reperfusion injury. They can cause tissue damages by at least 3 major mechanisms: (1) oxygen free radical release; (2) degranulation of elastase and proteases; and (3) release of arachidonic acid metabolites and platelet activating factors.62
An intimate link between cytokines and oxidative stress has recently been established, in which transgenic mice overexpressing TNF- increased the production of hydroxyl radical and impaired the antioxidant capacity of MnSOD.63 IL-6 can also induce oxidative stress and endothelial dysfunction in a model of atherosclerosis via angiotensin II receptor.64 TNF-, IL-1ß, and interferon- increased production of superoxide anion, which reacts with NO to form peroxynitrite and in turn desensitizes myofilament to calcium, leading to myocardial contractile failure.65 Suematsu reported recently that TNF- directly induced mitochondrial ROS production within cardiac myocytes and caused mitochondrial DNA damage via a ceramide-dependent signaling.66
Abnormal activation of the nonphagocytic NAD(P)H oxidase in response to neurohormones and cytokine activation (eg, angiotensin II, norepinephrine, TNF-) is also a major source of ROS. ROS, with its potentiation role in physiological signaling, has also been shown to contribute to the development of cardiac myocyte hypertrophy. Furthermore, the subsequent chronic remodeling processes including fibrosis, collagen deposition, and matrix metalloproteinase activation are all dependent on ROS released during the phenotypic transformation of fibroblasts to myofibroblasts. The latter is particularly associated with pathological fibrosis, hallmarks of progression toward end-stage heart failure.18,19,67
Initiation of Wound Healing
The acute remodeling process mediated by cytokines and inflammatory cells in the infarcted myocardium also initiate the wound repair process. This includes phagocytosis and resorption of the necrotic tissue, survival, and hypertrophy of the surviving myocytes, degradation and synthesis of matrix support such as collagens and integrins, proliferation of the myofibroblasts and angiogenesis/vasculogenesis, and, to a limited extent, progenitor cell proliferation.68–70
Interestingly, during the acute phase of myocardial infarction, cytokines such as TNF- and IL-1ß appear to play a protective and coordinating role for wound healing. Anti–IL-1ß treatment early postinfarction leads to poor wound healing and delayed collagen deposition.71 This is also concordant with the earlier observations that steroid treatment postmyocardial infarction leads to poor wound healing. Therefore, in balance, the acute and appropriate cytokine activation in the ischemically injured myocardium is fundamentally protective for the host, leading to improved wound healing and cell survival, at the expense of decreased contractility.
|
Chronic Remodeling Postinfarction |
|---|
|
TopAbstractIntroductionTriggers of Cytokine Production...Cytokines and Acute Myocardial...Chronic Remodeling...Clinical Implications: Cytokines...References |
|---|
After the initial increase of gene expression of cytokine such as TNF-
, IL-1ß, and IL-6 in the infarcted region, the cytokines normally begin to decrease toward baseline after 1 week.7 However, if the infarct size is large, or if there are other ongoing myocardial stress factors, the cytokine gene expression may remain significantly elevated or may recrudesce as a second wave of cytokine activation, particularly in the noninfarcted myocardium away from the original site of injury. Interestingly, the levels of late cytokine activation in the noninfarcted region correlated the best with the eventual left ventricular end-diastolic diameter measured at 20 weeks after infarction. Furthermore, expression of cytokines such as IL-1ß correlated best with subsequent collagen deposition in the noninfarcted myocardium. During this chronic phase of remodeling, cytokines such as IL-1ß are also found in macrophages, endothelial cells, and vascular smooth muscle cells in addition to myocytes. The recurrent or second phase of cytokine upregulation persist as the ventricle remodels, secondary to oxidative, mechanical, or neurohormonal stress, thus initiating a vicious cycle of stress-cytokine-stress. The vicious cycle of cytokine amplification can be attenuated significantly by the timely use of angiotensin-converting enzyme inhibitors, antioxidants, ß-blockers, or means to lower the mechanical load.72–74
Sustained Effects of Cytokines on Myocyte Morphology and Phenotype
The influence of cytokines on myocardial cell phenotype initiated during the acute phase of remodeling can continue during the chronic phase if the cytokine elevations are sustained. The processes of myocyte hypertrophy, myocyte apoptosis, and triggering of additional inflammatory cell signaling are particularly prominent. The best biological validation of this effect is through a variety of transgenic mice superexpressing TNF- in the myocardium.27,75,76 All these models consistently demonstrate myocardial hypertrophy, ultimately leading to dilated cardiomyopathy, inflammatory cell infiltrations, and increased interstitial fibrosis.
Cytokines and MMP Activation
The myocardium in the infarcted zone is ultimately replaced by scar tissue after gradual resorption of the necrotic tissue. Elevated cytokines also promote interstitial fibrosis and collagen deposition in the contralateral noninfarct zone. These remodeling processes involve synthesis and degradation of collagens as major components of the extracellular matrix, and, most important, mediators of the matrix remodeling are the MMPs. MMPs are present in the myocardial interstitium normally in the inactive form and can be readily activated within minutes of ischemia by free radicals, cytokines, and hypoxia, and they can be counter-regulated to a certain extent by tissue inhibitors of MMPs or TIMPs.77 Cytokines such as TNF- and IL-1ß can upregulate and activate MMPs that are initially responsible for collagen degradation and, subsequently, matrix deposition (Figure 1).
Studies in cultured neonatal and cardiac fibroblasts showed that IL-1ß decreases the expression of procollagens 1(I), 2(I), and 1(III) mRNA and increases MMP-13 (type I collagenase), MMP-2 (gelatinase A), and MMP-9 (gelatinase B) protein levels.78 TNF can, in addition, increase the mRNA expression for pro–MMP-3. In fact, 2 activators of MMPs—extracellular MMP inducer and membrane-type MMP—have been shown to be present in myocytes and are upregulated in myocardial infarction and failure.79 In transgenic mice overexpressing TNF, which develops dilated cardiomyopathy with time, their myocardium demonstrates increased MMP activity by gelatin zymography.
Interestingly, the hearts expressing highest levels of MMP-2 and MMP-9 proteins also have the most amount of collagen deposition and impaired diastolic function.80 Anti–TNF- treatment with adenoviral vector-expressing soluble TNF- p55 receptor attenuated MMP-2 and MMP-9 expression, decreased collagen synthesis, and corrected left ventricle diastolic dysfunction.
It is possible that MMP inhibition presents an interesting novel strategy in attenuating cardiac remodeling postinfarction. Initial testing with MMP inhibitors with activity against a broad spectrum of MMP showed positive results in mice,81 but an unfortunate side effect is that it may also inhibit angiogenesis.82 A more selective MMP inhibitor reduced scar thinning, reduced left ventricle chamber dilatation, and increases angiogenesis in the infarcted area.83 Recently, we have tested inhibitors of the proinflammatory MMP, elastase, and found that elastase inhibition can significantly improve the ventricular function and remodeling in an ischemic model.84 This confirms our earlier testing of this strategy in blocking inflammation and ventricular function in a model of myocarditis.85
Cytokines and Collagen Production
The cardiac matrix is an elaborate network of interconnected proteins, including collagen, elastin, and fibronectin, interacting with integrins and focal adhesion kinases at the cell/matrix junction. The collagen degradation and production postinfarction constitute the most dominant protein change in the myocardial matrix. Cytokines play an important role in regulating collagen deposition, including TNF, transforming growth factor (TGF-ß), and osteopontin.
After myocardial infarction in a rat model, expression of TNF-, IL-1ß, IL-6, TGF-ß1, and TGF-ß3 as expected are increased maximally by 2-fold at 1 week after myocardial infarction.86 These increases in cytokines correlate closely to the subsequent deposition of type I and type III collagens, and TGF-ß3 appears to play a particularly active role in the regulation of late collagen deposition.68 TNF- can also independently induce AT1 receptor upregulation, enhancing angiotensin II-mediated effects in favor of fibrosis.87
Osteopontin (OPN), also called cytokine Eta-1, is also expressed in the myocardium and plays an important role in postmyocardial infarction remodeling by promoting collagen synthesis and accumulation. Osteopontin, a cell-secreted adhesive glycophosphoprotein with embedded RGD motif, interacts with integrins vß3, vß5, vß1, and CD44 receptors. OPN is a multifunctional protein that can interact with fibronectin and collagen, suggesting a possible role in matrix organization or stability. OPN–/– (osteopontin-deficient) mice demonstrate disorganization of matrix and alterations in collagen fibrillogenesis. Increased expression of OPN postmyocardial infarction most likely coordinates remodeling by promoting collagen synthesis and accumulation through regulation of MMP activity via PKC-zeta.88,89
Cytokines and Integrins
The interaction of matrix with the myocyte can take place through a number of nodes, the most important of which is integrin. On the myocytes, integrin ß1 is associated with anchoring of the myocyte in its matrix. ß1 is found in 2 isoforms—a ß1D form, which exists in the adult myocyte, is important for firm anchoring of myocyte in the matrix and leads to effective mechanical advantage during contraction.70 A ß1A form exists in the fetal myocytes and promotes mobility and proliferation at the expense of efficient contractility. On exposure to cytokines such as TNF, the ß1D isoform is transitioned to the fetal ß1A isoform (Figure 2). This breaks the usual anchor of the myocyte to the matrix and promotes myocyte mobility. This transition is obliterated in the TNF-–/– knockout mice, despite cardiac injury such as infarction.70 However, integrin ß3 is found mainly in newly formed blood vessels and is also under cytokine control. This may provide 1 mechanism by which cytokines regulate the angiogenic pathways as well postinfarction, affecting the angiogenic potential.
|
Cytokines and Angiogenesis and Cell Regeneration Postinfarction
Part of the remodeling process postmyocardial infarction also involves regeneration of the lost components of the myocardium— blood vessels and cellular components such as the myocyte. The previous notion that after cardiac injury, the tissue will only be replaced by an inert scar is now overturned by current evidence support the fact that the heart can regenerate some of these components spontaneously and can be enhanced for an even more favorable remodeling.69
More recent studies suggest that cytokines elaborated during myocardial infarction can set the stage for subsequent angiogenesis. In a postinfarction model, expression of isoform VEGF120 was found at days 1 and 4 after myocardial infarction, whereas isoforms VEGF164 and VEGF188 along with expression of TNF- and iNOS were noted for a much longer period of time.59 These findings suggest that angiogenic factors are elaborated at the same time as proinflammatory cytokines to mediate vascular repair. Macrophages may also participate in angiogenesis; a macrophage-derived peptide, PR39, inhibited the ubiquitin-proteasome–dependent degradation of hypoxia-inducible factor-1- protein, resulting in accelerated formation of vascular structures in vitro and increased myocardial vasculature in mice.90
Chemokines are chemotactic cytokines important in regulating angiogenesis. One class of the chemokine is the "CXC" chemokines, which contain the 2 amino terminal cysteines are separated by a single nonconserved amino acid residue. CXC chemokines that contain the so-called ELR motif, such as IL-8, are potent angiogenic factors, whereas CXC chemokines that lack the ELR motif, such as interferon-inducible protein 10 (IP-10), are potent angiostatic factors. In the first hours of reperfusion, TNF- release from mast cells induces IP-10 synthesis in the microvascular endothelium. IP-10 expression inhibits angiogenic activity, until the injured area is débrided and a fibrin-based provisional matrix is formed. After the first 24 hours of reperfusion, TGF-ß–mediated IP-10 downregulation shifts the balance toward angiogenesis. Monocyte-derived macrophages, mast cells, and myofibroblasts secrete proteases and growth factors necessary for neovessel formation and optimal repair. In addition, TGF-ß potently upregulates ß-FGF and VEGF expression in endothelial cell and smooth muscle cells, thus enhancing angiogenic activity.
Furthermore, bone marrow cells from adult humans contain endothelial precursors with phenotypic and functional characteristics of embryonic hemangioblasts, and these can be used to directly induce new blood vessel formation in the infarct bed (vasculogenesis) and proliferation of preexisting vasculature (angiogenesis) after experimental myocardial infarction.91 The neoangiogenesis resulted in decreased apoptosis of hypertrophied myocytes in the peri-infarct region, long-term salvage and survival of viable myocardium, reduction in collagen deposition, and sustained improvement in cardiac function.
Inflammatory mediators may induce recruitment of blood-derived primitive stem cells in the healing infarct, which may differentiate into endothelial cells and even lead to limited myocardial regeneration. The mechanisms by which cytokine cascade is activated in the infarcted myocardium have been recently elucidated. Several hematopoietic growth factors including IL-3, IL-6, granulocyte macrophage colony-stimulating factors, G-CSF, and stem cell factor have been reported to be positive regulators of granulopoiesis and act at different stages of myeloid cell development. G-CSF plays a critical role in regulation of proliferation, differentiation, and survival of myeloid progenitor cells. G-CSF also causes a marked increase in the release of hematopoietic stem cells into the peripheral blood circulation, a process termed mobilization. Recently, G-CSF has been reported to improve cardiac function and reduces mortality after acute MI. Although the mechanism by which G-CSF ameliorates cardiac dysfunction is not fully understood, there is the possibility that G-CSF may regenerate cardiac myocytes and blood vessels through mobilization of bone marrow stem cells. In the future, cytokine-mediated regeneration therapy may evolve to be a novel therapeutic strategy for myocardial infarction.51
The hematopoietic growth factor EPO has been found to mediate repair and regeneration after brain and spinal cord injury, including the recruitment of stem cells into the region of damage. The EPO receptor interestingly is expressed in the fetal and adult heart as well. In models of myocardial ischemia and infarction, the administration of EPO has shown significant benefit by preventing myocyte apoptosis and attenuating deterioration in hemodynamic function. This benefit may also accrue from the mobilization of circulating stem cells, as observed in brain injury.52
|
Clinical Implications: Cytokines as Diagnostic and Prognostic Markers and Potential Targets for Therapy |
|---|
|
TopAbstractIntroductionTriggers of Cytokine Production...Cytokines and Acute Myocardial...Chronic Remodeling...Clinical Implications: Cytokines...References |
|---|
From the foregoing discussion, we can see that cytokines such as TNF are produced in significant quantities from the multiple sources postmyocardial infarction. They have effects on inflammatory cells, myocytes, and the matrix. These effects are pleiotropic and depend on the balance of other factors, the timing of release, and cell types involved. Therefore, the resulting phenotype can be very diverse.
More recently, the concept of inflammatory markers as a predictor of heart failure has gained more momentum. In the Framingham Heart Study, elderly patients who exhibited spontaneously elevated levels of inflammatory cytokines, including CRP, TNF, and particularly IL-6, have shown a much higher propensity for heart failure.92
In a Finnish clinical study postmyocardial infarction, IL-6 levels increased by 44% and peaked at 24 hours.93 Peak IL-6 levels correlated positively with area under the curve of creatine kinase MB mass, peak troponin T level, and procollagen type III aminoterminal peptide measured at discharge. IL-6 is thus a potential marker of myocardium undergoing stress but may, in turn, regulate subsequent collagen formation and thus remodel the left ventricle after acute myocardial infarction.
However, the recent failure of TNF- inhibitors in the treatment of CHF highlights the complexity of trying to inhibit this pleiotropic pathway in the heart, despite the success in the therapy of other inflammatory diseases. Therefore, for the cytokines to be a true therapeutic target, one would have to define the timing, the quantity, and what other cofactors need to be present to favorably influence the outcome. Until then, it is much better to treat the causative triggers of inflammation than to broadly block the effectors. However, the fact that many of the current modulators of benefit postinfarction already have important antiinflammatory activities, including angiotensin-converting enzyme inhibitors and ß-blockers, suggests that ultimately they converge on the inflammatory mechanisms as part of the mechanism to exert their benefit in contractility, survival, and remodeling.94–96
|
Acknowledgments |
|---|
Supported in part by grants from the Heart and Stroke Foundation (HSF) of Ontario, the Canadian Institutes of Health Research (CIHR), CHFNET, and TACTICS Partnership Programs of the HSF and CIHR. Dr. Liu holds the Heart & Stroke/Polo Chair Professor of Medicine and Physiology at the University of Toronto. Dr. Nian is a CIHR TACTICS research fellow. Drs. Khaper and Lee are recipients of the CIHR postdoctoral fellowship awards.
|
Footnotes |
|---|
Original received April 11, 2003; resubmission received February 19, 2004; revised resubmission received April 19, 2004; accepted April 20, 2004.
|
References |
|---|
|
TopAbstractIntroductionTriggers of Cytokine Production...Cytokines and Acute Myocardial...Chronic Remodeling...Clinical Implications: Cytokines...References |
|---|
1. White HD, Norris RM, Brown MA, Brandt PWT, Whitelock RML, Wild C. Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation. 1987; 76: 44–51.
2. Kapadia SR, Oral H, Lee J, Nakano M, Taffet GE, Mann DL. Hemodynamic regulation of tumor necrosis factor-alpha gene and protein expression in adult feline myocardium. Circ Res. 1997; 81: 187–195.
3. Kapadia S, Lee J, Torre-Amione G, Birdsall HH, Ma TS, Mann DL. Tumor necrosis factor-alpha gene and protein expression in adult feline myocardium after endotoxin administration. J Clin Invest. 1995; 96: 1042–1052.[Medline] [Order article via Infotrieve]
4. Mann DL. Stress-activated cytokines and the heart: from adaptation to maladaptation. Ann Rev Physiol. 2003; 65: 81–101.[CrossRef][Medline] [Order article via Infotrieve]
5. Deten A, Volz HC, Briest W, Zimmer HG. Cardiac cytokine expression is upregulated in the acute phase after myocardial infarction. Experimental studies in rats. Cardiovasc Res. 2002; 55: 329–340.
6. Irwin M, Mak S, Mann D, Qu R, Dawood F, Wen WH, Penninger J, Liu P. Tissue expression and immunolocalization of tumour necrosis factor-alpha in post infarction-dysfunctional myocardium. Circulation. 1999; 99: 1492–1498.
7. Ono K, Matsumori A, Shioi T, Furukawa Y, Sasayama S. Cytokine gene expression after myocardial infarction in rat hearts: possible implication in left ventricular remodeling. Circulation. 1998; 98: 149–156.
8. Gwechenberger M, Mendoza LH, Youker KA, Frangogiannis NG, Smith CW, Michael LH, Entman ML. Cardiac myocytes produce interleukin-6 in culture and in viable border zone of reperfused infarctions. Circulation. 1999; 99: 546–551.
9. Beg AA, Baltimore D. An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science. 1996; 274: 782–784.
10. Murakami M, Hibi M, Nakagawa N, Nakagawa T, Yasukawa K, Yamanishi K, Taga T, Kishimoto T. IL-6-induced homodimerization of gp130 and associated activation of a tyrosine kinase. Science. 1993; 260: 1808–1810.
11. Hirota H, Yoshida K, Kishimoto T, Taga T. Continuous activation of gp130, a signal-transducing receptor component for interleukin 6-related cytokines, causes myocardial hypertrophy in mice. Proc Natl Acad Sci U S A. 1995; 92: 4862–4866.
12. Shiomi T, Tsutsui H, Hayashidani S, Suematsu N, Ikeuchi M, Wen J, Ishibashi M, Kubota T, Egashira K, Takeshita A. Pioglitazone, a peroxisome proliferator-activated receptor-gamma agonist, attenuates left ventricular remodeling and failure after experimental myocardial infarction. Circulation. 2002; 106: 3126–3132.
13. Yue Tl, Chen J, Bao W, Narayanan PK, Bril A, Jiang W, Lysko PG, Gu JL, Boyce R, Zimmerman DM, Hart TK, Buckingham RE, Ohlstein EH. In vivo myocardial protection from ischemia/reperfusion injury by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. Circulation. 2001; 104: 2588–2594.
14. Meldrum DR, Dinarello CA, Cleveland JCJ, Cain BS, Shames BD, Meng X, Harken AH. Hydrogen peroxide induces tumor necrosis factor alpha-mediated cardiac injury by a p38 mitogen activated protein kinase-dependent mechanisms. Surgery. 1998; 124: 291–296.[Medline] [Order article via Infotrieve]
15. Nakamura K, Fushimi K, Kouchi H, Mihara K, Miyazaki M, Ohe T, Namba M. Inhibitory effects of antioxidants on neonatal rat cardiac myocyte hypertrophy induced by tumor necrosis factor-alpha and angiotensin II. Circulation. 1998; 98: 794–799.
16. Kukielka GL, Smith CW, Manning AM, Youker KA, Michael LH, Entman ML. Induction of interleukin-6 synthesis in the myocardium. Potential role in postreperfusion inflammatory injury. Circulation. 1995; 92: 1866–1875.
17. von Knethen A, Callsen D, Brune B. Superoxide attenuates macrophage apoptosis by NF-kappa B and AP-1 activation that promotes cyclooxygenase-2 expression. J Immunol. 1999; 163: 2858–2866.
18. Sia YT, Parker TG, Liu P, Tsoporis JN, Adam A, Rouleau JL. Improved post-myocardial infarction survival with probucol in rats: effects on left ventricular function, morphology, cardiac oxidative stress and cytokine expression. J Am Coll Cardiol. 2002; 39: 148–156.
19. Khaper N, Singal PK. Modulation of oxidative stress by a selective inhibition of angiotensin II type 1 receptors in MI-rats. J Am Coll Cardiol. 2001; 37: 1461–1466.
20. Nakamura H, Umemoto S, Naik G, Moe G, Takata S, Liu P, Matsuzaki M. Induction of left ventricular remodeling and dysfunction in the recipient heart after donor heart myocardial infarction: new insights into the pathologic role of tumor necrosis factor-alpha from a novel heterotopic transplant-coronary ligation rat model. J Am Coll Cardiol. 2003; 42: 173–181.
21. Kumar, A. G., Ballantyne C., M, Michael LH, Kukielka GL, Youker KA, Lindsey ML, Hawkins HK, Birdsall HH, MacKay CR, LaRosa GJ, Rossen RD, Smith CW, Entman ML. Induction of monocyte chemoattractant protein-1 in the small veins of the ischemic and reperfused canine myocardium. Circulation. 1997; 95: 693–700.
22. Kakio T, Matsumori A, Ono K, Ito H, Matsushima K, Sasayama S. Roles and relationship of macrophages and monocyte chemotactic and activating factor/monocyte chemoattractant protein-1 in the ischemic and reperfused rat heart. Lab Invest. 2000; 80: 1127–1136.[Medline] [Order article via Infotrieve]
23. Frangogiannis NG, Perrard JL, Mendoza LH, Burns AR, Lindsey ML, Ballantyne CM, Michael LH, Smith CW, Entman ML. Stem cell factor induction is associated with mast cell accumulation after canine myocardial ischemia and reperfusion. Circulation. 1998; 98: 687–698.
24. Palojoki E, Saraste A, Eriksson A, Pulkki K, Kallajoki M, Voipio-Pulkki LM, Tikkanen I. Cardiomyocyte apoptosis and ventricular remodeling after myocardial infarction in rats. Am J Physiol. 2001; 280: H2726–H2731.
25. Krown KA, Page MT, Nguyen C, Zechner D, Gutierrez V, Comstock KL, Glembotski CC, Quintana PJ, Sabbadini RA. Tumor necrosis factor alpha-induced apoptosis in cardiac myocytes. Involvement of the sphingolipid signaling cascade in cardiac cell death. J Clin Invest. 1996; 98: 2854–2865.[Medline] [Order article via Infotrieve]
26. Yokoyama T, Nakano M, Bednarczyk JL, McIntyre BW, Entman M, Mann DL. Tumor necrosis factor-alpha provokes a hypertrophic growth response in adult cardiac myocytes. Circulation. 1997; 95: 1247–1252.
27. Kubota T, McTiernan CF, Frye CS, Slawson SE, Lemster BH, Koretsky AP, Demetris AJ, Feldman AM. Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor-alpha. Circ Res. 1997; 81: 627–635.
28. Frangogiannis NG, Smith CW, Entman ML. The inflammatory response in myocardial infarction. Cardiovasc Res. 2002; 53: 31–47.
29. MacEwan DJ. TNF receptor subtype signaling: differences and cellular consequences. Cell Signal. 2002; 14: 477–492.[CrossRef][Medline] [Order article via Infotrieve]
30. Baxter GT, Kuo RC, Jupp OJ, Vandenabeele P, MacEwan DJ. Tumor necrosis factor-alpha mediates both apoptotic cell death and cell proliferation in a human hematopoietic cell line dependent on mitotic activity and receptor subtype expression. J Biol Chem. 1999; 274: 9539–9547.
31. Ashkenazi A, Dixit VM. Apoptosis control by death and decoy receptors. Curr Opin Cell Biol. 1999; 11: 255–260.[CrossRef][Medline] [Order article via Infotrieve]
32. Wallach D, Varfolomeev EE, Malinin NL, Goltsev YV, Kovalenko AV, Boldin MP. Tumor necrosis factor receptor and Fas signaling mechanisms. Annu Rev Immunol. 1999; 17: 331–367.[CrossRef][Medline] [Order article via Infotrieve]
33. Chinnaiyan AM, O’Rourke K, Yu GL, Lyons RH, Garg M, Duan DR, Xing L, Gentz R, Ni J, Dixit VM. Signal transduction by DR3, a death domain-containing receptor related to TNFR-1 and CD95. Science. 1996; 274: 990–992.
34. Pan G, O’Rourke K, Chinnaiyan AM, Gentz R, Ebner R, Ni J, Dixit VM. The receptor for the cytotoxic ligand TRAIL. Science. 1997; 276: 111–113.
35. Pan G, Ni J, Wei YF, Yu G, Gentz R, Dixit VM. An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science. 1997; 277: 815–818.
36. Pan G, Ni J, Yu G, Wei YF, Dixit VM. TRUNDD, a new member of the TRAIL receptor family that antagonizes TRAIL signalling. FEBS Letter. 1998; 424: 41–45.[CrossRef][Medline] [Order article via Infotrieve]
37. Tartaglia LA, Ayres TM, Wong GH, Goeddel DV. A novel domain within the 55kd TNF receptor signals cell death. Cell. 1993; 74: 845–853.[CrossRef][Medline] [Order article via Infotrieve]
38. MacEwan DJ. TNF ligands and receptors - a matter of life and death. Br J Pharmacol. 2002; 135: 855–875.[CrossRef][Medline] [Order article via Infotrieve]
39. Adam-Klages S, Adam D, Wiegmann K, Struve S, Kolanus W, Schneider-Mergener J, Kronke M. FAN, a novel WD-repeat protein, couples the p55 TNF-receptor to neutral sphingomyelinase. Cell. 1996; 86: 937–947.[CrossRef][Medline] [Order article via Infotrieve]
40. Dbaibo GS, El-Assaad W, Krikorian A, Liu B, Diab K, Idriss NZ, El-Sabban M, Driscoll TA, Perry DK, Hannun YA. Ceramide generation by two distinct pathways in tumor necrosis factor alpha-induced cell death. FEBS Lett. 2001; 503: 7–12.[CrossRef][Medline] [Order article via Infotrieve]
41. Jarvis WD, Kolesnick RN, Fornari FA, Traylor RS, Gewirtz DA, Grant S. Induction of apoptotic DNA damage and cell death by activation of the sphingomyelin pathway. Proc Natl Acad Sci U S A. 1994; 91: 73–77.
42. Pimentel-Muinos FX, Seed B. Regulated commitment of TNF receptor signaling: a molecular switch for death or activation. Immunity. 1999; 11: 783–793.[CrossRef][Medline] [Order article via Infotrieve]
43. Malinin NL, Boldin MP, Kovalenko AV, Wallach D. MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95. Nature. 1997; 385: 540–544.[CrossRef][Medline] [Order article via Infotrieve]
44. Liu ZG, Hsu H, Goeddel DV, Karin M. Dissection of TNF receptor 1 effector function: JNK activation is not linked to apoptosis while NF-kB activation prevents cell death. Cell. 1996; 87: 565–576.[CrossRef][Medline] [Order article via Infotrieve]
45. Natoli G, Costanzo A, Ianni A, Templeton DJ, Woodgett JR, Balsano C, Levrero. Activation of SAPK/JNK by TNF receptor 1 through a noncytotoxic TRAF2-dependent pathway. Science. 1997; 275: 200–203.
46. Baud V, Liu ZG, Bennett B, Suzuki N, Xia Y, Karin M. Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain. Genes Devel. 1999; 13: 1297–1308.
47. Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB. NF-kappaB activation by tumour necrosis factor requires the Akt serine- threonine kinase. Nature. 1999; 401: 82–85.[CrossRef][Medline] [Order article via Infotrieve]
48. Kubota T, McTiernan CF, Frye CS, Demetris AJ, Feldman AM. Cardiac-specific overexpression of tumor necrosis factor-alpha causes lethal myocarditis in transgenic mice. J Cardiac Failure. 1997; 3: 117–124.[CrossRef][Medline] [Order article via Infotrieve]
49. Hirano T. Interleukin 6 and its receptor: ten years later. Int Rev Immunol. 1998; 16: 249–284.[Medline] [Order article via Infotrieve]
50. Gallucci RM, Simeonova PP, Matheson JM, Kommineni C, Guriel JL, Sugawara T, Luster MI. Impaired cutaneous wound healing in interleukin-6-deficient and immunosuppressed mice. FASEB J. 2000; 14: 2525–2531.
51. Takano H, Ohtsuka M, Akazawa H, Toko H, Harada M, Hasegawa H, Nagai T, Komuro I. Pleiotropic effects of cytokines on acute myocardial infarction: G-CSF as a novel therapy for acute myocardial infarction. Curr Pharmacol Descriptions. 2003; 9: 1121–1127.[CrossRef]
52. Calvillo L, Latini R, Kajstura J, Leri A, Anversa P, Ghezzi P, Salio M, Cerami A, Brines M. Recombinant human erythropoietin protects the myocardium from ischemia-reperfusion injury and promotes beneficial remodeling. Proc Natl Acad Sci U S A. 2003; 100: 4802–4806.
53. Yokoyama T, Vaca L, Rossen RD, Durante W, Hazarika P, Mann DL. Cellular basis for the negative inotropic effects of tumor necrosis factor-alpha in the adult mammalian heart. J Clin Invest. 1993; 92: 2303–2312.[Medline] [Order article via Infotrieve]
54. Goldhaber JI. Free radicals enhance Na+/Ca2+ exchange in ventricular myocytes. Am J Physiol. 1996; 271: H823–H833.[Medline] [Order article via Infotrieve]
55. Krown KA, Yasui K, Brooker MJ, Dubin AE, Nguyen C, Harris GL, McDonough PM, Glembotski CC, Palade PT, Sabbadini RA. TNF alpha receptor expression in rat cardiac myocytes: TNF alpha inhibition of L-type Ca2+ current and Ca2+ transients. FEBS Lett. 1995; 376: 24–30.[CrossRef][Medline] [Order article via Infotrieve]
56. Oral H, Dorn GWn, Mann DL. Sphingosine mediates the immediate negative inotropic effects of tumor necrosis factor-alpha in the adult mammalian cardiac myocyte. J Biol Chem. 1997; 272: 4836–4842.
57. Lee SH, Wolf PL, Escudero R, Deutsch R, Jamieson SW, Thistlethwaite PA. Early expression of angiogenesis factors in acute myocardial ischemia and infarction. N Engl J Med. 2000; 342: 626–633.
58. Kranz A, Rau C, Kochs M, Waltenberger J. Elevation of vascular endothelial growth factor-A serum levels following acute myocardial infarction. Evidence for its origin and functional significance. J Mol Cell Cardiol. 2000; 32: 65–72.[CrossRef][Medline] [Order article via Infotrieve]
59. Heba G, Krzeminski T, Porc M, Grzyb J, Dembinska-Kiec A. Relation between expression of TNF alpha, iNOS, VEGF mRNA and development of heart failure after experimental myocardial infarction in rats. J Physiol Pharmacol. 2001; 52: 39–52.[Medline] [Order article via Infotrieve]
60. Ebnet K, Vestweber D. Molecular mechanisms that control leukocyte extravasation: the selectins and the chemokines. Histochem Cell Biol. 1999; 112: 1–23.[CrossRef][Medline] [Order article via Infotrieve]
61. Yuan SY, Wu MH, Ustinova EE, Guo M, Tinsley JH, De Lanerolle P, Xu W. Myosin light chain phosphorylation in neutrophil-stimulated coronary microvascular leakage. Circ Res. 2002; 90: 1214–1221.
62. Jordan JE, Zhao ZQ, Vinten-Johansen J. The role of neutrophils in myocardial ischemia-reperfusion injury. Cardiovasc Res. 1999; 43: 860–878.
63. Machida Y, Kubota T, Kawamura N, Funakoshi H, Ide T, Utsumi H, Li YY, Feldman AM, Tsutsui H, Shimokawa H, Takeshita A. Overexpression of tumor necrosis factor -alpha increases production of hydroxyl radical in murine myocardium. Am J Physiol Heart Circ Physiol. 2002; 284: H449–H455.[Medline] [Order article via Infotrieve]
64. Wassmann S, Michaela S, Strehlov K, Schmid A, Schieffer B, Bohm M, Nickenig G. Interleukin-6 induces oxidative stress and endothelial dysfunction by overexpression of the angiotensin II type 1 receptor. Circ Res. 2004; 94: 1–8.
65. Ferdinandy P, Danial H, Ambrus I, Rothery RA, Schulz R. Peroxynitrite is a major contributor to cytokine-induced myocardial contractile failure. Circ Res. 2000; 87: 241–247.
66. Suematsu N, Tsutsui H, Wen J, Kang D, et al. Oxidative stress mediated tumor necrosis factor alpha induced mitochondrial DNA damage and dysfunction in cardiac myocytes. Circulation. 2003; 107: 1418–1423.
67. Sun Y, Zhang J, Lu L, Chen SS, Quinn MT, Weber KT. Aldosterone-induced inflammation in the rat heart: role of oxidative stress. Am J Pathol. 2002; 161: 1773–1781.
68. Deten A, Holzl A, Leicht M, Barth W, Zimmer HG. Changes in extracellular matrix and in transforming growth factor beta isoforms after coronary artery ligation in rats. J Mol Cell Cardiol. 2001; 33: 1191–1207.[CrossRef][Medline] [Order article via Infotrieve]
69. Anversa P, Nadal-Ginard B. Myocyte renewal and ventricular remodelling. Nature. 2002; 415: 240–243.[CrossRef][Medline] [Order article via Infotrieve]
70. Sun M, Opavsky A, Stewart DJ, Rabinovtich M, Dawood F, Wen WH, Liu PP. Temporal response and localization of integrins beta-1 and beta-2 in the heart following myocardial infarction: Regulation by cytokines. Circulation. 2003; 107: 1046–1052.
71. Hwang MW, Matsumori A, Furukawa Y, Ono K, Okada M, Iwasaki A, Hara M, Miyamoto T, Touma M, Sasayama S. Neutralization of interleukin-1beta in the acute phase of myocardial infarction promotes the progression of left ventricular remodeling. J Am Coll Cardiol. 2001; 38: 1546–1553.
72. Wei GC, Sirois MG, Qu R, Liu P, Rouleau JL. Subacute and chronic effects of quinapril on cardiac cytokine expression, remodeling, and function after myocardial infarction in the rat. J Cardiovasc Pharmacol. 2002; 39: 842–850.[CrossRef][Medline] [Order article via Infotrieve]
73. Sia YT, Liu PP, Rouleau JL. Beneficial effects of the long-term use of the antioxidant probucol in heart failure in the rat. Circulation. 2002; 105: 2549–2555.
74. Sia YT, Parker TG, Tsoporis JN, Liu P, Adam A, Rouleau JL. Long-term effects of carvedilol on left ventricular function, remodeling, and expression of cardiac cytokines after large myocardial infarction in the rat. J Cardiovasc Pharmacol. 2002; 39: 73–87.[CrossRef][Medline] [Order article via Infotrieve]
75. Bryant D, Becker L, Richardson J, Shelton J, Franco F, Peshock R, Thompson M, Giroir B. Cardiac failure in transgenic mice with myocardial expression of tumor necrosis factor-alpha. Circulation. 1998; 97: 1375–1381.
76. Sivasubramanian N, Coker ML, Kurrelmeyer KM, MacLellan WR, DeMayo FJ, Spinale FG, Mann DL. Left ventricular remodeling in transgenic mice with cardiac restricted overexpression of tumor necrosis factor. Circulation. 2001; 104: 826–831.
77. Creemers EE, Cleutjens JP, Smits JF, Daemen MJ. Matrix metalloproteinase inhibition after myocardial infarction: a new approach to prevent heart failure? Circ Res. 2001; 89: 201–210.
78. Siwik DA, Chang DL, Colucci WS. Interleukin-1 beta and tumor necrosis factor-alpha decrease collagen synthesis and increase matrix metalloproteinase activity in cardiac fibroblasts in vitro. Circ Res. 2000; 86: 1259–1265.
79. Spinale FG, Coker ML, Heung LJ, Bond BR, Gunasinghe HR, Etoh T, Goldberg AT, Zellner JL, Crumbley AJ. A matrix metalloproteinase induction/activation system exists in the human left ventricular myocardium and is upregulated in heart failure. Circulation. 2000; 102: 1944–1949.
80. Li YY, Feng YQ, Kadokami T, McTiernan CF, Draviam R, Watkins SC, Feldman AM. Myocardial extracellular matrix remodeling in transgenic mice overexpressing tumor necrosis factor alpha can be modulated by anti- tumor necrosis factor alpha therapy. Proc Natl Acad Sci U S A. 2000; 97: 12746–12751.
81. Rohde LE, Ducharme A, Arroyo LH, Aikawa M, Sukhova GH, Lopez-Anaya A, McClure KF, Mitchell PG, Libby P, Lee RT. Matrix metalloproteinase inhibition attenuates early left ventricular enlargement after experimental myocardial infarction in mice. Circulation. 2000; 99: 3063–3070.
82. Heymans S, Luttun A, Nuyens D, Theilmeier G, Creemers E, Moons L, Dyspersin GD, Cleutjens JP, Shipley M, Angellilo A, Levi M, Nube O, Baker A, Keshet E, Lupu F, Herbert JM, Smits JF, Shapiro SD, Baes M, Borgers M, Collen D, Daemen MJ, Carmeliet P. Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure. Nat Med. 2000; 5: 1135–1142.[CrossRef]
83. Lindsey ML, Gannon J, Aikawa M, Schoen FJ, Rabkin E, Lopresti-Morrow L, Crawford J, Black S, Libby P, Mitchell PG, Lee RT. Selective matrix metalloproteinase inhibition reduces left ventricular remodeling but does not inhibit angiogenesis after myocardial infarction. Circulation. 2000; 105: 753–758.[CrossRef]
84. Ohta K, Nakajima T, Cheah AY, Zaidi SH, Kaviani N, Dawood F, You XM, Liu P, Husain M, Rabinovitch M. Elafin overexpressing mice have improved cardiac function after myocardial infarction. Am J Physiol. 2003;[Epub ahead of print].
85. Lee JK, Zaidi SHE, Liu P, Dawood F, A. Y. L. C, Wen WH, Saiki Y, Rabinovitch M. A serine elastase inhibitor reduces inflammation and fibrosis and preserves cardiac function following experimental murine myocarditis. Nat Med. 1998; 4: 1383–1391.[CrossRef][Medline] [Order article via Infotrieve]
86. Yue P, Massie BM, Simpson PC, Long CS. Cytokine expression increases in nonmyocytes from rats with postinfarction heart failure. Am J Physiol. 1998; 275: H250–H258.[Medline] [Order article via Infotrieve]
87. Peng J, Gurantz D, Tran V, Cowling RT, Greenberg BH. Tumor necrosis factor-alpha-induced AT1 receptor upregulation enhances angiotensin II-mediated cardiac fibroblast responses that favor fibrosis. Circ Res. 2002; 91: 1119–1126.
88. Trueblood NA, Xie Z, Communal C, Sam F, Ngoy S, Liaw L, Jenkins AW, Wang J, Sawyer DB, Bing OH, Apstein CS, Colucci WS, Singh K. Exaggerated left ventricular dilation and reduced collagen deposition after myocardial infarction in mice lacking osteopontin. Circ Res. 2001; 88: 1080–1087.
89. Xie Z, Singh M, Siwik DA, Joyner WL, Singh K. Osteopontin inhibits interleukin-1beta-stimulated increases in matrix metalloproteinase activity in adult rat cardiac fibroblasts: role of protein kinase C-zeta. J Biol Chem. 2003; 278: 48546–48552.
90. Li J, Post M, Volk R, Gao Y, Li M, Metais C, Sato K, Tsai J, Aird W, Rosenberg RD, Hampton TG, Sellke F, Carmeliet P, Simons M. PR39, a peptide regulator of angiogenesis. Nat Med. 2000; 6: 49–55.[CrossRef][Medline] [Order article via Infotrieve]
91. Kocher AA, Schuster MD, Szabolcs MJ, Takuma S, Burkhoff D, Wang J, Homma S, Edwards NM, Itescu S. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med. 2001; 7: 430–436.[CrossRef][Medline] [Order article via Infotrieve]
92. Vasan RS, Sullivan LM, Roubenoff R, Dinarello CA, Harris T, Benjamin EJ, Sawyer DB, Levy D, Wilson PW, D’Agostino RB, Framingham Heart Study. Inflammatory markers and risk of heart failure in elderly subjects without prior myocardial infarction: the Framingham Heart Study. Circulation. 2003; 107: 1486–1491.
93. Puhakka M, Magga J, Hietakorpi S, Penttila I, Uusimaa P, Risteli J, Peuhkurinen K. Interleukin-6 and tumor necrosis factor alpha in relation to myocardial infarct size and collagen formation. J Cardiac Failure. 2003; 9: 325–332.[CrossRef][Medline] [Order article via Infotrieve]
94. Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJJ, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC, Investigators TS. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. N Engl J Med. 1992; 327: 669–677.[Abstract]
95. van Gilst WH, Kingma JH, Peels KH, Dambrink JH, St John Sutton M. Which patient benefits from early angiotensin-converting enzyme inhibition after myocardial infarction? Results of one-year serial echocardiographic follow-up from the Captopril and Thrombolysis Study (CATS). J Am Coll Cardiol. 1996; 28: 114–121.[Abstract]
96. Warren SE, Royal HD, Markis JE, Grossman W, McKay RG. Time course of left ventricular dilation after myocardial infarction: influence of infarct-related artery and success of coronary thrombolysis. J Am Coll Cardiol. 1988; 11: 12–19.[Abstract]
This article has been cited by other articles:
 |
|
 |
|
  J. Butler, A. Kalogeropoulos, V. Georgiopoulou, N. de Rekeneire, N. Rodondi, A. L. Smith, U. Hoffmann, A. Kanaya, A. B. Newman, S. B. Kritchevsky, et al. Serum Resistin Concentrations and Risk of New Onset Heart Failure in Older Persons: The Health, Aging, and Body Composition (Health ABC) Study Arterioscler. Thromb. Vasc. Biol., July 1, 2009; 29(7): 1144 - 1149. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Chua, L.-T. Chang, C.-K. Sun, J.-J. Sheu, F.-Y. Lee, A. A. Youssef, C.-H. Yang, C.-J. Wu, and H.-K. Yip Time Courses of Subcellular Signal Transduction and Cellular Apoptosis in Remote Viable Myocardium of Rat Left Ventricles Following Acute Myocardial Infarction: Role of Pharmacomodulation Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2009; 14(2): 104 - 115. [Abstract] [PDF]
|
|
|
|
 |
|
 K. Venkatachalam, B. Venkatesan, A. J. Valente, P. C. Melby, S. Nandish, J. E. B. Reusch, R. A. Clark, and B. Chandrasekar WISP1, a Pro-mitogenic, Pro-survival Factor, Mediates Tumor Necrosis Factor-{alpha} (TNF-{alpha})-stimulated Cardiac Fibroblast Proliferation but Inhibits TNF-{alpha}-induced Cardiomyocyte Death J. Biol. Chem., May 22, 2009; 284(21): 14414 - 14427. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Orn, C. Manhenke, T. Ueland, J. K. Damas, T. E. Mollnes, T. Edvardsen, P. Aukrust, and K. Dickstein C-reactive protein, infarct size, microvascular obstruction, and left-ventricular remodelling following acute myocardial infarction Eur. Heart J., May 2, 2009; 30(10): 1180 - 1186. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Mohri, Y. Fujio, M. Obana, T. Iwakura, K. Matsuda, M. Maeda, and J. Azuma Signals Through Glycoprotein 130 Regulate the Endothelial Differentiation of Cardiac Stem Cells Arterioscler. Thromb. Vasc. Biol., May 1, 2009; 29(5): 754 - 760. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Marfella, C. Di Filippo, M. Portoghese, F. Ferraraccio, M. R. Rizzo, M. Siniscalchi, E. Musacchio, M. D'Amico, F. Rossi, and G. Paolisso Tight Glycemic Control Reduces Heart Inflammation and Remodeling During Acute Myocardial Infarction in Hyperglycemic Patients J. Am. Coll. Cardiol., April 21, 2009; 53(16): 1425 - 1436. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. J. Hong, M. H. Jeong, Y. H. Choi, J. S. Ko, M. G. Lee, W. Y. Kang, S. E. Lee, S. H. Kim, K. H. Park, D. S. Sim, et al. Plaque characteristics in culprit lesions and inflammatory status in diabetic acute coronary syndrome patients. J. Am. Coll. Cardiol. Img., March 1, 2009; 2(3): 339 - 349. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Kohno, T. Anzai, K. Naito, T. Miyasho, M. Okamoto, H. Yokota, S. Yamada, Y. Maekawa, T. Takahashi, T. Yoshikawa, et al. Role of high-mobility group box 1 protein in post-infarction healing process and left ventricular remodelling Cardiovasc Res, February 15, 2009; 81(3): 565 - 573. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hori and K. Nishida Oxidative stress and left ventricular remodelling after myocardial infarction Cardiovasc Res, February 15, 2009; 81(3): 457 - 464. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Diez and G. Ertl A translational approach to myocardial remodelling Cardiovasc Res, February 15, 2009; 81(3): 409 - 411. [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Shaw, M. K.H. Shah, S. G. Williams, and J. E. Fildes Immunological mechanisms of pentoxifylline in chronic heart failure Eur J Heart Fail, February 1, 2009; 11(2): 113 - 118. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Heymans, E. Hirsch, S. D. Anker, P. Aukrust, J.-L. Balligand, J. W. Cohen-Tervaert, H. Drexler, G. Filippatos, S. B. Felix, L. Gullestad, et al. Inflammation as a therapeutic target in heart failure? A scientific statement from the Translational Research Committee of the Heart Failure Association of the European Society of Cardiology Eur J Heart Fail, February 1, 2009; 11(2): 119 - 129. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Huang, J. Rubinstein, A. R. Prieto, L. V. Thang, and D. H. Wang Transient Receptor Potential Vanilloid Gene Deletion Exacerbates Inflammation and Atypical Cardiac Remodeling After Myocardial Infarction Hypertension, February 1, 2009; 53(2): 243 - 250. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Xiao, Q. She, Y. Wang, K. Luo, Y. Yin, R. Hu, and K. Huang Effect of allopurinol on cardiomyocyte apoptosis in rats after myocardial infarction Eur J Heart Fail, January 1, 2009; 11(1): 20 - 27. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Chao Toll-like receptor signaling: a critical modulator of cell survival and ischemic injury in the heart Am J Physiol Heart Circ Physiol, January 1, 2009; 296(1): H1 - H12. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. L. Urish, J. B. Vella, M. Okada, B. M. Deasy, K. Tobita, B. B. Keller, B. Cao, J. D. Piganelli, and J. Huard Antioxidant Levels Represent a Major Determinant in the Regenerative Capacity of Muscle Stem Cells Mol. Biol. Cell, January 1, 2009; 20(1): 509 - 520. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Naito, T. Anzai, Y. Sugano, Y. Maekawa, T. Kohno, T. Yoshikawa, K. Matsuno, and S. Ogawa Differential Effects of GM-CSF and G-CSF on Infiltration of Dendritic Cells during Early Left Ventricular Remodeling after Myocardial Infarction J. Immunol., October 15, 2008; 181(8): 5691 - 5701. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Bujak, M. Dobaczewski, K. Chatila, L. H. Mendoza, N. Li, A. Reddy, and N. G. Frangogiannis Interleukin-1 Receptor Type I Signaling Critically Regulates Infarct Healing and Cardiac Remodeling Am. J. Pathol., July 1, 2008; 173(1): 57 - 67. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-S. Silvestre, Z. Mallat, A. Tedgui, and B. I. Levy Post-ischaemic neovascularization and inflammation Cardiovasc Res, May 1, 2008; 78(2): 242 - 249. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Rodriguez-Porcel, W. Cai, O. Gheysens, J. K. Willmann, K. Chen, H. Wang, I. Y. Chen, L. He, J. C. Wu, Z.-b. Li, et al. Imaging of VEGF Receptor in a Rat Myocardial Infarction Model Using PET J. Nucl. Med., April 1, 2008; 49(4): 667 - 673. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Yang, Y. Ma, W. Han, J. Li, Y. Xiang, F. Liu, X. Ma, J. Zhang, Z. Fu, Y.-D. Su, et al. Age-related differences in postinfarct left ventricular rupture and remodeling Am J Physiol Heart Circ Physiol, April 1, 2008; 294(4): H1815 - H1822. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Huebener, T. Abou-Khamis, P. Zymek, M. Bujak, X. Ying, K. Chatila, S. Haudek, G. Thakker, and N. G. Frangogiannis CD44 Is Critically Involved in Infarct Healing by Regulating the Inflammatory and Fibrotic Response J. Immunol., February 15, 2008; 180(4): 2625 - 2633. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Kubo, T.-S. Li, R. Suzuki, B. Shirasawa, N. Morikage, M. Ohshima, S.-L. Qin, and K. Hamano Hypoxic preconditioning increases survival and angiogenic potency of peripheral blood mononuclear cells via oxidative stress resistance Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H590 - H595. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Rafiq, M. Hanscom, K. Valerie, S. F. Steinberg, and A. Sabri Novel Mode for Neutrophil Protease Cathepsin G Mediated Signaling: Membrane Shedding of Epidermal Growth Factor Is Required for Cardiomyocyte Anoikis Circ. Res., January 4, 2008; 102(1): 32 - 41. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Kaneda, M. Miyamae, S. Sugioka, C. Okusa, Y. Inamura, N. Domae, J. Kotani, and V. M. Figueredo Sevoflurane Enhances Ethanol-Induced Cardiac Preconditioning Through Modulation of Protein Kinase C, Mitochondrial KATP Channels, and Nitric Oxide Synthase, in Guinea Pig Hearts Anesth. Analg., January 1, 2008; 106(1): 9 - 16. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W Wojakowski, M Kucia, M Kazmierski, M Z Ratajczak, and M Tendera Circulating progenitor cells in stable coronary heart disease and acute coronary syndromes: relevant reparatory mechanism? Heart, January 1, 2008; 94(1): 27 - 33. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Freeling, K. Wattier, C. LaCroix, and Y.-F. Li Neostigmine and pilocarpine attenuated tumour necrosis factor {alpha} expression and cardiac hypertrophy in the heart with pressure overload Exp Physiol, January 1, 2008; 93(1): 75 - 82. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. P. Yang, S. Mattagajasingh, S. Su, G. Chen, Z. Cai, K. Fox-Talbot, K. Irani, and L. C. Becker Fractalkine Upregulates Intercellular Adhesion Molecule-1 in Endothelial Cells Through CX3CR1 and the Jak Stat5 Pathway Circ. Res., November 9, 2007; 101(10): 1001 - 1008. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. G. Spinale Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function Physiol Rev, October 1, 2007; 87(4): 1285 - 1342. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Khan, V. K. Kutala, D. S. Vikram, S. Wisel, S. M. Chacko, M. L. Kuppusamy, I. K. Mohan, J. L. Zweier, P. Kwiatkowski, and P. Kuppusamy Skeletal myoblasts transplanted in the ischemic myocardium enhance in situ oxygenation and recovery of contractile function Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2129 - H2139. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. A. Turner, R. S. Mughal, P. Warburton, D. J. O'Regan, S. G. Ball, and K. E. Porter Mechanism of TNF{alpha}-induced IL-1{alpha}, IL-1{beta} and IL-6 expression in human cardiac fibroblasts: Effects of statins and thiazolidinediones Cardiovasc Res, October 1, 2007; 76(1): 81 - 90. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Kitsios and E. Zintzaras Genetic Variation associated with Ischemic Heart Failure: A HuGE Review and Meta-Analysis Am. J. Epidemiol., September 15, 2007; 166(6): 619 - 633. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Cimini, S. Fazel, S. Zhuo, M. Xaymardan, H. Fujii, R. D. Weisel, and R.-K. Li c-Kit Dysfunction Impairs Myocardial Healing After Infarction Circulation, September 11, 2007; 116(11_suppl): I-77 - I-82. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. V. Ramana, R. Tammali, A. B. M. Reddy, A. Bhatnagar, and S. K. Srivastava Aldose Reductase-Regulated Tumor Necrosis Factor-{alpha} Production Is Essential for High Glucose-Induced Vascular Smooth Muscle Cell Growth Endocrinology, September 1, 2007; 148(9): 4371 - 4384. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. A. Jaffer, P. Libby, and R. Weissleder Molecular Imaging of Cardiovascular Disease Circulation, August 28, 2007; 116(9): 1052 - 1061. [Full Text] [PDF]
|
|
|
|
 |
|
 H. F. Kramer and L. J. Goodyear Exercise, MAPK, and NF-{kappa}B signaling in skeletal muscle J Appl Physiol, July 1, 2007; 103(1): 388 - 395. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Fernandez-Velasco, G. Ruiz-Hurtado, O. Hurtado, M. A. Moro, and C. Delgado TNF-{alpha} downregulates transient outward potassium current in rat ventricular myocytes through iNOS overexpression and oxidant species generation Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H238 - H245. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Zymek, D.-Y. Nah, M. Bujak, G. Ren, A. Koerting, T. Leucker, P. Huebener, G. Taffet, M. Entman, and N. G. Frangogiannis Interleukin-10 is not a critical regulator of infarct healing and left ventricular remodeling Cardiovasc Res, May 1, 2007; 74(2): 313 - 322. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-L. Li, M.-L. Zhuo, D. Wang, A.-B. Wang, H. Cai, L.-H. Sun, Q. Yang, Y. Huang, Y.-S. Wei, P. P. Liu, et al. Targeted Cardiac Overexpression of A20 Improves Left Ventricular Performance and Reduces Compensatory Hypertrophy After Myocardial Infarction Circulation, April 10, 2007; 115(14): 1885 - 1894. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Aronson, H. Hammerman, M. R. Kapeliovich, A. Suleiman, Y. Agmon, R. Beyar, W. Markiewicz, and M. Suleiman Fasting Glucose in Acute Myocardial Infarction: Incremental value for long-term mortality and relationship with left ventricular systolic function Diabetes Care, April 1, 2007; 30(4): 960 - 966. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Westermann, S. Rutschow, S. Jager, A. Linderer, S. Anker, A. Riad, T. Unger, H.-P. Schultheiss, M. Pauschinger, and C. Tschope Contributions of Inflammation and Cardiac Matrix Metalloproteinase Activity to Cardiac Failure in Diabetic Cardiomyopathy: The Role of Angiotensin Type 1 Receptor Antagonism Diabetes, March 1, 2007; 56(3): 641 - 646. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Yndestad, L. E. Vinge, R. Bjornerheim, T. Ueland, J. E. Wang, S. S. Froland, H. Attramadal, P. Aukrust, and E. Oie Thalidomide attenuates the development of fibrosis during post-infarction myocardial remodelling in rats Eur J Heart Fail, December 1, 2006; 8(8): 790 - 796. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Ince, T. C. Rehders, S. Kische, S. Drawert, E. Adolf, T. Kleinfeldt, M. Petzsch, and C. A. Nienaber G-CSF in the setting of acute myocardial infarction Eur. Heart J. Suppl., December 1, 2006; 8(suppl_H): H40 - H45. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Zoccali, G. Tripepi, and F. Mallamaci Dissecting Inflammation in ESRD: Do Cytokines and C-Reactive Protein Have a Complementary Prognostic Value for Mortality in Dialysis Patients? J. Am. Soc. Nephrol., December 1, 2006; 17(12_suppl_3): S169 - S173. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. D. Thakker, N. G. Frangogiannis, M. Bujak, P. Zymek, J. W. Gaubatz, A. K. Reddy, G. Taffet, L. H. Michael, M. L. Entman, and C. M. Ballantyne Effects of diet-induced obesity on inflammation and remodeling after myocardial infarction Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2504 - H2514. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. W. Cheng, K. Obata, M. Kuzuya, H. Izawa, K. Nakamura, E. Asai, T. Nagasaka, M. Saka, T. Kimata, A. Noda, et al. Elastolytic Cathepsin Induction/Activation System Exists in Myocardium and Is Upregulated in Hypertensive Heart Failure Hypertension, November 1, 2006; 48(5): 979 - 987. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Postiglione, S. Montagnani, P. Ladogana, C. Castaldo, G. Di Spigna, E. M. Bruno, M. Turano, L. De Santo, G. Cudemo, S. Cocozza, et al. Granulocyte Macrophage-Colony Stimulating Factor receptor expression on human cardiomyocytes from end-stage heart failure patients Eur J Heart Fail, October 1, 2006; 8(6): 564 - 570. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. G. Spinale, G. P. Escobar, J. W. Hendrick, L. L. Clark, S. S. Camens, J. P. Mingoia, C. G. Squires, R. E. Stroud, and J. S. Ikonomidis Chronic Matrix Metalloproteinase Inhibition Following Myocardial Infarction in Mice: Differential Effects on Short and Long-Term Survival J. Pharmacol. Exp. Ther., September 1, 2006; 318(3): 966 - 973. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Clerk and P. H. Sugden Inflame My Heart (by p38-MAPK) Circ. Res., September 1, 2006; 99(5): 455 - 458. [Full Text] [PDF]
|
|
|
|
|
|
O. Tenhunen, J. Rysa, M. Ilves, Y. Soini, H. Ruskoaho, and H. Leskinen Identification of Cell Cycle Regulatory and Inflammatory Genes As Predominant Targets of p38 Mitogen-Activated Protein Kinase in the Heart Circ. Res., September 1, 2006; 99(5): 485 - 493. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ikeda, R. K. Kundu, S. Ikeda, M. Kobara, H. Matsubara, and T. Quertermous Glia Maturation Factor-{gamma} Is Preferentially Expressed in Microvascular Endothelial and Inflammatory Cells and Modulates Actin Cytoskeleton Reorganization Circ. Res., August 18, 2006; 99(4): 424 - 433. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Kodama, Y. Kitta, T. Nakamura, H. Takano, K. Umetani, D. Fujioka, Y. Saito, K.-i. Kawabata, J.-e. Obata, A. Mende, et al. Atorvastatin Increases Plasma Soluble Fms-Like Tyrosine Kinase-1 and Decreases Vascular Endothelial Growth Factor and Placental Growth Factor in Association With Improvement of Ventricular Function in Acute Myocardial Infarction J. Am. Coll. Cardiol., July 4, 2006; 48(1): 43 - 50. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Wang, Q. Hu, Y. Nakamura, J. Lee, G. Zhang, A. H.L. From, and J. Zhang The Role of the Sca-1+/CD31- Cardiac Progenitor Cell Population in Postinfarction Left Ventricular Remodeling Stem Cells, July 1, 2006; 24(7): 1779 - 1788. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Niu, A. Azfer, and P. E. Kolattukudy Monocyte-specific Bcl-2 expression attenuates inflammation and heart failure in monocyte chemoattractant protein-1 (MCP-1)-induced cardiomyopathy Cardiovasc Res, July 1, 2006; 71(1): 139 - 148. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. V. Ramana, A. Bhatnagar, S. Srivastava, U. C. Yadav, S. Awasthi, Y. C. Awasthi, and S. K. Srivastava Mitogenic Responses of Vascular Smooth Muscle Cells to Lipid Peroxidation-derived Aldehyde 4-Hydroxy-trans-2-nonenal (HNE): ROLE OF ALDOSE REDUCTASE-CATALYZED REDUCTION OF THE HNE-GLUTATHIONE CONJUGATES IN REGULATING CELL GROWTH J. Biol. Chem., June 30, 2006; 281(26): 17652 - 17660. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Petermann, C. Mayer, J. Stypmann, M. L. Biniossek, D. J. Tobin, M. A. Engelen, T. Dandekar, T. Grune, L. Schild, C. Peters, et al. Lysosomal, cytoskeletal, and metabolic alterations in cardiomyopathy of cathepsin L knockout mice FASEB J, June 1, 2006; 20(8): 1266 - 1268. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. A. Jankowska, P. Ponikowski, M. F. Piepoli, W. Banasiak, S. D. Anker, and P. A. Poole-Wilson Autonomic imbalance and immune activation in chronic heart failure - Pathophysiological links Cardiovasc Res, June 1, 2006; 70(3): 434 - 445. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Roy, S. Khanna, D. E. Kuhn, C. Rink, W. T. Williams, J. L. Zweier, and C. K. Sen Transcriptome analysis of the ischemia-reperfused remodeling myocardium: temporal changes in inflammation and extracellular matrix Physiol Genomics, May 16, 2006; 25(3): 364 - 374. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q.-Y. Zhang, J.-B. Ge, J.-Z. Chen, J.-H. Zhu, L.-H. Zhang, C.-P. Lau, and H.-F. Tse Mast Cell Contributes to Cardiomyocyte Apoptosis after Coronary Microembolization J. Histochem. Cytochem., May 1, 2006; 54(5): 515 - 523. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 The PREAMI Investigators* Effects of Angiotensin-Converting Enzyme Inhibition With Perindopril on Left Ventricular Remodeling and Clinical Outcome: Results of the Randomized Perindopril and Remodeling in Elderly With Acute Myocardial Infarction (PREAMI) Study. Arch Intern Med, March 27, 2006; 166(6): 659 - 666. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Suleiman, R. Khatib, Y. Agmon, R. Mahamid, M. Boulos, M. Kapeliovich, Y. Levy, R. Beyar, W. Markiewicz, H. Hammerman, et al. Early Inflammation and Risk of Long-Term Development of Heart Failure and Mortality in Survivors of Acute Myocardial Infarction: Predictive Role of C-Reactive Protein J. Am. Coll. Cardiol., March 7, 2006; 47(5): 962 - 968. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Carluccio, P. Biagioli, G. Alunni, A. Murrone, C. Giombolini, T. Ragni, P. N. Marino, G. Reboldi, and G. Ambrosio Patients With Hibernating Myocardium Show Altered Left Ventricular Volumes and Shape, Which Revert After Revascularization: Evidence That Dyssynergy Might Directly Induce Cardiac Remodeling J. Am. Coll. Cardiol., March 7, 2006; 47(5): 969 - 977. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nahrendorf, K. Hu, S. Frantz, F. A. Jaffer, C.-H. Tung, K.-H. Hiller, S. Voll, P. Nordbeck, D. Sosnovik, S. Gattenlohner, et al. Factor XIII Deficiency Causes Cardiac Rupture, Impairs Wound Healing, and Aggravates Cardiac Remodeling in Mice With Myocardial Infarction Circulation, March 7, 2006; 113(9): 1196 - 1202. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Hasegawa, H. Takano, K. Iwanaga, M. Ohtsuka, Y. Qin, Y. Niitsuma, K. Ueda, T. Toyoda, H. Tadokoro, and I. Komuro Cardioprotective Effects of Granulocyte Colony-Stimulating Factor in Swine With Chronic Myocardial Ischemia J. Am. Coll. Cardiol., February 21, 2006; 47(4): 842 - 849. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. B. Ayach, M. Yoshimitsu, F. Dawood, M. Sun, S. Arab, M. Chen, K. Higuchi, C. Siatskas, P. Lee, H. Lim, et al. Stem cell factor receptor induces progenitor and natural killer cell-mediated cardiac survival and repair after myocardial infarction PNAS, February 14, 2006; 103(7): 2304 - 2309. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. J. Armstrong, D. A. Morrow, and M. S. Sabatine Inflammatory Biomarkers in Acute Coronary Syndromes: Part I: Introduction and Cytokines Circulation, February 14, 2006; 113(6): e72 - e75. [Full Text] [PDF]
|
|
|
|
|
|
X. Liu, A. S. Pachori, C. A. Ward, J. P. Davis, M. Gnecchi, D. Kong, L. Zhang, J. Murduck, S.-F. Yet, M. A. Perrella, et al. Heme oxygenase-1 (HO-1) inhibits postmyocardial infarct remodeling and restores ventricular function FASEB J, February 1, 2006; 20(2): 207 - 216. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Matsumoto-Ida, Y. Takimoto, T. Aoyama, M. Akao, T. Takeda, and T. Kita Activation of TGF-{beta}1-TAK1-p38 MAPK pathway in spared cardiomyocytes is involved in left ventricular remodeling after myocardial infarction in rats Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H709 - H715. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Li and J. F. Engelhardt Interleukin-1beta Induction of NF{kappa}B Is Partially Regulated by H2O2-mediated Activation of NF{kappa}B-inducing Kinase J. Biol. Chem., January 20, 2006; 281(3): 1495 - 1505. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. F. Bonvini, T. Hendiri, and E. Camenzind Inflammatory response post-myocardial infarction and reperfusion: a new therapeutic target? Eur. Heart J. Suppl., October 1, 2005; 7(suppl_I): I27 - I36. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Zhang, Y.-J. Xu, H. K. Saini, B. Turan, P. P. Liu, and N. S. Dhalla Pentoxifylline attenuates cardiac dysfunction and reduces TNF-{alpha} level in ischemic-reperfused heart Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H832 - H839. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. G. Frangogiannis, G. Ren, O. Dewald, P. Zymek, S. Haudek, A. Koerting, K. Winkelmann, L. H. Michael, J. Lawler, and M. L. Entman Critical Role of Endogenous Thrombospondin-1 in Preventing Expansion of Healing Myocardial Infarcts Circulation, June 7, 2005; 111(22): 2935 - 2942. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-L. Su, K.-P. Lai, C.-A. Chen, C.-Y. Yang, P.-S. Chen, C.-C. Chang, C.-H. Chou, C.-L. Hu, M.-L. Kuo, C.-Y. Hsieh, et al. A Novel Peptide Specifically Binding to Interleukin-6 Receptor (gp80) Inhibits Angiogenesis and Tumor Growth Cancer Res., June 1, 2005; 65(11): 4827 - 4835. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. C. Becker Yin and Yang of MCP-1 Circ. Res., April 29, 2005; 96(8): 812 - 814. [Full Text] [PDF]
|
|
|
|
|
|
O. Dewald, P. Zymek, K. Winkelmann, A. Koerting, G. Ren, T. Abou-Khamis, L. H. Michael, B. J. Rollins, M. L. Entman, and N. G. Frangogiannis CCL2/Monocyte Chemoattractant Protein-1 Regulates Inflammatory Responses Critical to Healing Myocardial Infarcts Circ. Res., April 29, 2005; 96(8): 881 - 889. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. van Westerloo, T. van der Poll, R. B. Felder, R. M. Weiss, Z.-H. Zhang, and J. Francis Acute Vagotomy Activates the Cholinergic Anti-Inflammatory Pathway Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H977 - H979. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Ikonomidis, J. W. Hendrick, A. M. Parkhurst, A. R. Herron, P. G. Escobar, K. B. Dowdy, R. E. Stroud, E. Hapke, M. R. Zile, and F. G. Spinale Accelerated LV remodeling after myocardial infarction in TIMP-1-deficient mice: effects of exogenous MMP inhibition Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H149 - H158. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. B. Buxton Cytokines and Late Preconditioning Cardiovasc Res, October 1, 2004; 64(1): 6 - 8. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||