Epigenetic Modulation of EPCs (p 180)
Stripping endothelial progenitor cells of repressive epigenetic marks improves their ability to repair damaged hearts, report Thal et al.
Endothelial progenitor cells (EPCs) are among a number of cell types that have been investigated for their heart-repairing qualities. Previous studies have shown that these cells, by secreting growth factors, promote the generation of new blood vessels in hearts injured by infarction. The ultimate aim for such cell therapies, however, is to induce not only new vessels but new myocardium as well. Thal et al now find that EPCs can differentiate into cardiomyocytes in vivo if repressive epigenetic marks are removed from their genomes and activating marks are retained. The team treated EPCs with drugs that prevent both DNA methylation—a silencing mark—and the removal of histone acetylation—an activating mark—and then transplanted these cells into infarcted mouse hearts. The cells spontaneously differentiated into cardiomyocytes at the injury site, which the authors suggest was because the cells were more epigenetically “open” to respond to environmental differentiation cues. Furthermore, the treated cells were also better than their untreated counterparts at promoting blood vessel growth. Therefore, this epigenetic treatment could give an all-round boost to the regenerative efficacy of EPCs.
Adipocyte TRPC Channels and Adiponectin (p 191)
Blocking calcium channels in adipocytes boosts secretion of the insulin-sensitizing adipokine adiponectin, report Sukumar et al.
Adiponectin is a cytokine secreted from adipose tissue and is known to have anti-inflammatory, antiatherosclerotic, and insulin-sensitizing effects. Indeed, low blood levels of adiponectin are associated with diabetes, hypertension, and endothelial dysfunction. Boosting adiponectin might therefore be a strategy for treating cardiovascular disorders, and Sukumar et al have found one way of doing it. The researchers were studying ion channels in fat cells and discovered that antibodies that blocked the activity of two calcium channels—TRPC1 and TRPC5—not only reduced calcium entry into the cells but also stopped adiponectin secretion. This same effect was observed in organ culture of fat tissue and in live mice by knock-down of TRPC. The team also discovered that certain dietary fatty acids commonly found in oily fish and vegetable oils could inhibit the TRPC channels and thus prompt adiponectin secretion. These fatty acids have been shown to reduce the risk of coronary heart disease, heart attack, and other cardiovascular disorders. The current research thus reveals a mechanism for the cardioprotection offered by these fatty acids, and suggests that other inhibitors of TRPC might offer similar protection.
Cx43 Phosphorylation and VSMC Proliferation (p 201)
Phosphorylation of connexin 43 by the kinase MAPK causes blood vessel restriction, report Johnstone et al.
Dysregulated proliferation of vascular smooth muscle cells is a feature of plaque formation during atherosclerosis, and it is associated with changes in the expression and phosphorylation status of membrane protein connexin 43. Whether connexin 43 phosphorylation could actually promote smooth muscle cell proliferation, however, was unknown. One known promoter of vascular smooth muscle cell proliferation was the protein kinase MAPK. However, the mechanism of action of MAPK was also unknown. Johnstone et al have now linked these two disparate threads of information and discovered that MAPK phosphorylation of connexin 43 is a necessary mechanism for vascular smooth muscle cell proliferation. They found that connexin 43 interacts with the cell cycle regulatory protein cyclin E in vivo and that this interaction requires phosphorylation of connexin 43 by MAPK. Furthermore, mice that carried a mutant form of connexin 43, which could not be phosphorylated by MAPK, displayed a markedly reduced interaction between cyclin E and connexin 43, reduced smooth muscle cell proliferation, and diminished thickening of blood vessel walls. Targeting this phosphorylation event or protein interaction could be a strategy for antiatherosclerotic therapies, say the authors.
Written by Ruth Williams
- © 2012 American Heart Association, Inc.