β-Myosin Heavy Chain in Smaller Myocytes (p 629)
A classic hypertrophy-associated protein might in fact be antihypertrophic, say Lopez et al.
The β-myosin heavy chain protein (β-MyHC) is expressed in myocytes of the fetus, but after birth it is largely replaced by α-MyHC. During periods of cardiac hypertrophy, however, β-MyHC is once again activated. It was thought that this reactivation was part of the pathological process, but Lopez et al have now discovered that cardiac myocytes expressing β-MyHC do not undergo hypertrophy. The team analyzed between 10 000 and 20 000 cardiomyocytes from several hypertrophic mouse hearts and found that while in comparison with normal hearts, the number of cells expressing β-MyHC went up, these cells remained small. It was the cells that did not express β-MyHC that grew. All cells continued to express α-MyHC, so it appears to be the presence of β-MyHC rather than a switch from α-MyHC to β-MyHC that prevented cell growth. The team also found that β-MyHC expressing cells tended to be located in particular regions of the heart, including the papillary muscle, perivascular regions, and the base of the junction between left and right ventricles. Additional characterization of these β-MyHC expressing cells might help reveal how they avoid hypertrophy, and could offer clues for future antihypertrophic therapies.
SIRT1 Protects Endothelial Function (p 639)
Zhou et al suggest a possible means for improving vascular function and prolonging life.
Mice that lack a signal transduction protein, p66Shc, are protected against atherosclerosis and diabetes-related vascular endothelial dysfunction. As a result, they enjoy a longer lifespan. Similarly, mice that over-express the chromatin remodeling protein SIRT1 also suffer less atherosclerosis and have better endothelial function. Zhou et al decided to see whether these 2 lifespan-controlling proteins somehow interact with one another. It turns out, they do. One clue was that in the aortas of diabetic mice, SIRT1 levels were decreased and p66Shc levels increased, while in the aortas of calorie-restricted mice – which have longer lifespans – SIRT1 was increased and p66Shc decreased. The team then showed that inhibition of SIRT1 in cultured vascular endothelial cells increased p66Shc expression. Conversely, over-expression of SIRT1, both in cultured cells and in vivo, decreased p66Shc expression. Finally the team confirmed that SIRT1 directly bound to the promoter region of the p66Shc gene and modified its chromatin to repress transcription. The authors suggest that this SIRT1-p66Shc interaction may be a novel therapeutic target for combating diabetes- and age-related cardiovascular disease.
miR-15 Family and Cardiomyocyte Proliferation (p 670)
A microRNA called miR-195 puts a stop to heart cell division, report Porrello et al
Immediately following birth, myocytes of the mammalian heart stop dividing and become terminally differentiated. This exit from the cell cycle corresponds with a loss of the regenerative capacity of the heart. Porrello et al wondered whether microRNAs (miRs) might be involved in regulating this cell cycle arrest since miRs are known to regulate a wide range of developmental processes. The team found that 71 miRs were either up or down-regulated in neonatal mouse heart cells, of which miR-195 was the most highly upregulated. mIR-195 is a member of a family of miRs that are known to regulate the cell cycle in other tissues. Here, the team showed that miR-195 regulated the cycling of cardiac myocytes. They showed that knockdown of miR-195 in neonatal mice led to an increase in the number of mitotic heart cells, while premature expression of miR-195 interfered with normal heart development. miR-195 also suppressed the expression of a number of mRNAs involved in cell cycle progression. Understanding the precise mechanism of miR-195 and other regulators of cardiac myocyte cell cycle may be useful for therapeutically prompting adult cardiac myocytes to proliferate after heart injuries, say the team.
- © 2011 American Heart Association, Inc.