Abstract 19599: Loss of Alpha-Catenins Increases Nuclear Yap and Cardiomyocyte Proliferation and Improves Cardiac Function Following Myocardial Infarction
Background: Shortly after birth, muscle cells of the mammalian heart lose their ability to divide. Thus, they are unable to effectively replace dying cells in the injured heart. The recent discovery that the transcriptional co-activator Yap is necessary and sufficient for cardiomyocyte proliferation has gained considerable attention. However, the upstream regulators that control Yap activity in the heart remain largely unknown. Objective: To investigate the role of α-catenins in the heart using cardiac-specific αE- and αT-catenin double knockout (α-cat DKO) mice.
Methods: We used two cardiac-specific Cre transgenes to delete both αE-catenin (Ctnna1) and αT-catenin (Ctnna3) genes either in the perinatal or in the adult heart, and performed a series of experiments to examine the role of α-catenins under normal and pathological conditions.
Results: Postnatal depletion of α-catenins caused a decrease in cardiomyocyte size and an increase in cardiomyocyte number in the α-cat DKO mice. Increased nuclear Yap and the cell cycle regulator cyclin D1 accompanied cardiomyocyte proliferation in the α-cat DKO hearts. In comparison, ablation of α-catenins in the adult heart did not result in a proliferative phenotype. However, inactivation of α-catenins improved cardiac function following myocardial infarction. Increased nuclear Yap along with increased number of cells in cytokinesis indicated that cardiomyocyte proliferation contributed, at least in part, to the improved contractile function in the α-cat DKO heart following injury.
Conclusions: These studies demonstrate that α-catenins are critical regulators of Yap, a transcriptional co-activator essential for cardiomyocyte proliferation. Furthermore, we provide proof-of-concept that inhibiting α-catenins might be a useful strategy to promote myocardial regeneration following injury.
- © 2012 by American Heart Association, Inc.