Ionic Currents in Intact Hearts (p 203)
Ramos-Franco et al measure action potential-associated ionic currents in whole mouse hearts.
Much of what is known about the electrophysiological properties of the heart has come from patch clamp recordings of individual isolated cardiac myocytes. But in the heart, cardiomyocytes don’t act alone: they form an electrically interconnected syncytium. The recent development of a technique called loose patch clamping now enables the study of ionic currents in multicellular preparations of cardiac muscle, but the approach has not been applied to whole hearts—until now. Using intact perfused mouse hearts, Ramos-Franco and colleagues performed loose patch clamping, but also took the technique a step further. Rather than simply recording electrical activity, they manipulated the function of a particular type of ion channel—the L-type calcium channel—to determine its contribution to various phases of the cardiac action potential. They used a photodegradable inhibitor of the channel such that, with the flick of a light switch, the channels were activated. This approach, called loose patch photolysis (LPP), revealed that the L-type channel—long-considered to be active during phase 2 of the action potential—is in fact activated during phase 1. The use of whole heart LPP with other photosensitive compounds could greatly extend our understanding of cardiac electrophysiology in both normal and disease states, the authors say.
(Pro)renin Receptor and LDL Metabolism (p 222)
The (pro)renin receptor regulates uptake of “bad” cholesterol into human cells, report Lu et al.
The (pro)renin receptor (PRR) is considered to be an important component of the blood pressure regulating renin-angiotensin-aldosterone system. It binds (pro)renin—an enzyme that cleaves angiotensinogen to create angiotensin 1. Nevertheless, the physiological significance of the interaction of PRR with (pro)renin-PRR is unclear. For one thing, the interaction seems to require (pro)renin at concentrations well above those observed under normal conditions. Moreover, the PRR has been discovered recently to have (pro)renin-independent functions. Hence, to gain a clearer picture of the true physiological functions of PRR, Lu and colleagues performed unbiased immuno-precipitation experiments in human cells. They found that among the proteins that co-precipitated with PRR, was sortilin-1 (SORT1), which is known to bind low-density lipoproteins (LDLs) and transport them into cells. In agreement with this role of sortilin, they found that silencing of PRR reduced both the protein level of SORT1 and the cellular uptake of LDL. Interestingly however, the reduction of SORT1 was only partly responsible for the reduction of LDL uptake. It turned out that PRR silencing also directly suppressed levels of the canonical LDL receptor itself. These results reveal a hitherto unappreciated role of PRR in regulating LDL uptake that now warrants further analysis in vivo.
CDKN2B and Vascular Maturation (p 230)
Nanda et al investigate how CDKN2B contributes to cardiovascular disease.
In humans, the 9p21 chromosome locus contains the gene encoding CDKN2B—a cell cycle regulator—and has been linked to cardiovascular disease risk. To determine how the risk-associated allele at 9p21 might contribute to cardiovascular disease risk, Nanda and colleagues studied atherosclerotic plaques of deceased patients that were either homozygous or heterozygous for the risk variant. They found that compared with patients with normal genotypes, carriers of the risk allele had increased densities of microvessels in their plaques. However, these vessels appeared less mature: they tended to lack the smooth muscle cells (SMCs) that envelope normal vessels. The team went on to show that mice lacking a functional Cdkn2b gene did not recover from ischemic injury as well as control animals because their revascularized tissue contained a high burden of immature, SMC-lacking vessels. In vitro studies revealed that while a lack of Cdkn2b promoted angiogenic behavior in endothelial cells (ECs), it reduced the recruitment of SMC to the ECs. The team traced this defect to aberrant TGF-β signaling and found that correcting TGF-β expression reversed the defect. Taken together, these results suggest that targeting TGF-β or CDKN2B in individuals with the 9p21 risk allele might have clinical benefits.
- © 2016 American Heart Association, Inc.