Abstract 246: YAP1 Activation Suppresses Heart Failure Through Regulation of DNA Repair

Abstract

Introduction: The mammalian hearts including humans have a limited regenerative capacity. Activation of proliferation or related signaling pathways has been shown to reinstate cell renewal capacity of cardiomyocytes (CM) which is believed to ameliorate heart failure (HF). However, whether new CM are generated underlying cardiac regeneration in adult mammalian hearts upon damage is elusive. It is also unknown whether and by what mechanisms activation of CM proliferation benefits HF besides cardiac regeneration. Hypothesis: The protective role of cardiac cell cycle activation for damaged hearts could be independent of heart regeneration. Methods and Results: We show that cardiac specific activation of YAP1 , the terminal effector of the Hippo signaling pathway, suppressed HF and cardiac fibrosis induced by Lmna insufficiency ( Lmna HF). Although activation of YAP1 promoted G1 and S phase of cardiac cell cycle in disease hearts, CM did not undergo mitotic phase, a critical step for heart regeneration. RNAseq followed by signaling pathway analysis and validation showed that Fanconi anemia (FA) DNA repair pathway was activated by YAP1 . Cardiac DNA damage in Lmna HF was suppressed by YAP1 activation. Importantly, reduction of Fancd2 compromised the suppressive role of YAP1 in Lmna HF. Mechanistically, YAP1 promoted mono-ubiquitination of FANCD2 (ub-FANCD2) through promoting cell cycle. Conclusions: Our findings demonstrate that promoting cardiac DNA repair becomes a new therapeutic strategy against HF.