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 co-activator 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 α-catenins in the heart using cardiac-specific αE- and αT-catenin double knockout (α-cat DKO) mice.
Methods and Results: 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. Perinatal depletion of α-catenins increased cardiomyocyte number in the postnatal heart. Increased nuclear Yap and the cell cycle regulator cyclin D1 accompanied cardiomyocyte proliferation in the α-cat DKO hearts. Fetal genes were increased in the α-cat DKO hearts indicating a less mature cardiac gene expression profile. Knockdown (KD) of α-catenins in neonatal rat cardiomyocytes also resulted in increased proliferation, which could be blocked by KD of Yap. Finally, inactivation of α-catenins in the adult heart using an inducible Cre led to increased nuclear Yap and cardiomyocyte proliferation and improved contractility following myocardial infarction.
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.
- cardiac regeneration
- cell cycle progression
- animal model
- cardiac myocyte
- myocardial infarction
- Received May 27, 2014.
- Revision received October 9, 2014.
- Accepted October 10, 2014.