Acetylation Regulates YAP Subcellular Localization and Cardiac Regeneration - PROJECT SUMMARY Ischemic heart diseases, which include heart failure, are linked to systolic dysfunction resulting from the loss of cardiomyocytes (CMs). The ultimate therapeutic approach for this condition is the regeneration of new CMs. Recent studies on heart regeneration suggested that stimulating the natural division of CMs, known as mitosis, is a promising strategy for myocardium regeneration. YAP is a transcriptional cofactor that shuttles in and out of the nucleus in response to physiologic inputs. The Hippo pathway is a kinase cascade that suppresses YAP by phosphorylation, which prevents YAP from entering the nucleus. Our previous studies and others have shown that inhibition of the Hippo pathway causes YAP nuclear localization, promoting CM proliferation and suppressing pathologic remodeling in mice and pigs, suggesting that targeting the Hippo pathway could be a potential therapeutic approach for treating ischemic heart diseases. However, CM proliferation induced by the inhibition of the Hippo pathway is self-limiting, suggesting other mechanisms can regulate the function of YAP. In the pathophysiological context after myocardial infarction (MI), we found that YAP is transiently localized to the nucleus of CMs, which is associated with acetylation. YAP is acetylated by CBP/p300, but YAP deacetylation is regulated by SIRTs and its cofactor NAD+. Here, we propose that metabolic stresses regulate YAP acetylation through NAD+, which affects YAP activity and subcellular localization. We will test how the NAD+/SIRT1/2 axis regulates YAP acetylation in mouse models with myocardial infarction and investigate whether combined targeting the Hippo pathway and YAP acetylation can enhance cardiac regeneration more effectively than targeting either pathway alone. This mechanism involves a Hippo-independent, post- translational regulation of YAP activity called acetylation. Unlike the Hippo pathway-mediated YAP phosphorylation that occurs in the cytoplasm, we found YAP to be acetylated in the nucleus, representing an additional mechanism for YAP regulation. This comprehensive understanding of the mechanism of YAP in regulating cardiac regeneration and remodeling can lead to the development of more effective therapeutic strategies for treating ischemic heart diseases.
