Cardiac Cytoskeleton Sequesters Acetylated Yap In The Cytoplasm To Inhibit Cardiomyocyte Renewal After Myocardial Infarction

The Hippo pathway effector YAP is essential in cardiomyocyte proliferation and heart regeneration. How YAP responds to physiological conditions such as myocardial infarction (MI) is unclear. Here we show YAP transiently localizes to the nucleus of border zone CMs after MI. Nuclear YAP is acetylated by P300/CBP, and SIRTs deacetylation activity is decreased due to metabolic stress resulting from the injury. These mechanisms in conjunction results in increased acetylated YAP accumulation in the cytoplasm. After MI, the cardiac cytoskeleton is stabilized and sequesters cytoplasmic acetylated YAP, which reduces YAP activity and inhibits cardiomyocyte renewal. In a genetically engineered mouse model with a mutation that abolishes YAP acetylation, the mutant heart exhibits improved cardiac regeneration ability compared to the wild-type heart due to increased nuclear YAP localization. Together, we demonstrate that the injury-induced metabolic shift results in YAP acetylation, which translocates YAP to the cytoplasm in a manner independent of the Hippo pathway, and is detrimental to cardiac regeneration after MI.