Alpha-Catenins Control Cardiomyocyte Proliferation by Regulating Yap Activity

Rationale: 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 coactivator Yes-associated protein (Yap) is necessary and sufficient for cardiomyocyte proliferation has gained considerable attention. However, the upstream regulators and signaling pathways that control Yap activity in the heart are poorly understood. Objective: To investigate the role of alpha-catenins in the heart using cardiac-specific alpha E- and alpha T-catenin double knockout mice. Methods and Results: We used 2 cardiac-specific Cre transgenes to delete both alpha E-catenin (Ctnna1) and alpha T-catenin (Ctnna3) genes either in the perinatal or in the adult heart. Perinatal depletion of alpha-catenins increased cardiomyocyte number in the postnatal heart. Increased nuclear Yap and the cell cycle regulator cyclin D1 accompanied cardiomyocyte proliferation in the alpha-catenin double knockout hearts. Fetal genes were increased in the alpha-catenin double knockout hearts indicating a less mature cardiac gene expression profile. Knockdown of alpha-catenins in neonatal rat cardiomyocytes also resulted in increased proliferation, which could be blocked by knockdown of Yap. Finally, inactivation of alpha-catenins in the adult heart using an inducible Cre led to increased nuclear Yap and cardiomyocyte proliferation and improved contractility after myocardial infarction. Conclusions: These studies demonstrate that alpha-catenins are critical regulators of Yap, a transcriptional coactivator essential for cardiomyocyte proliferation. Furthermore, we provide proof of concept that inhibiting alpha-catenins might be a useful strategy to promote myocardial regeneration after injury.