YAP plays a critical role in myocardial recovery from myocarditis by suppressing IFN-γ signaling pathway

AIMS: Despite the limited resilience of adult mammalian hearts, the heart damaged by inflammation naturally heals in a majority of patients with myocarditis. Therefore, therapeutic activation of intrinsic healing capacity of the heart would be promising as regenerative medicine. Yes-associated protein 1 (YAP) determines organ size by regulating cell proliferation. However, the physiological roles of YAP activation in adult mammalian cardiomyocytes remain unclear. This study aimed to investigate the role of endogenous YAP activation in cardiac remodeling during myocarditis to clarify the molecular mechanisms underlying myocardial recovery. METHODS AND RESULTS: We demonstrate that YAP, which is activated in human cardiomyocytes during the myocardial remodeling after acute myocarditis, plays critical roles in myocardial healing. To elucidate the underlying mechanisms, we utilized a murine experimental autoimmune myocarditis (EAM) model. In cardiomyocyte-specific Yap1-conditional knockout (YAPCKO) mice, myocardial recovery is impaired after EAM with increased apoptotic cell death, fibrosis and ROS production, and reduced cardiomyocyte cell-cycle activity and capillary density. RNA-sequencing analysis demonstrated that IFN-γ/STAT1 signaling is activated in YAPCKO cardiomyocytes in myocarditis. IFN-γ blockade and cardiac-specific STAT1 knockdown restores the above-mentioned adverse phenotypic changes in YAPCKO hearts. Furthermore, in cultured adult mouse cardiomyocytes, the activation of YAP by GA-017, a Lats inhibitor, attenuated IFN-γ signal transduction. Mechanistically, YAP activation suppresses STAT1 nuclear localization and reduces STAT1-mediated transcription. CONCLUSION: Endogenous YAP acts as a negative regulator of IFN-γ/STAT1 signaling, promoting myocardial repair after myocarditis. Our findings presented here provide novel insights into the molecular regulation of myocardial healing, proposing a novel therapeutic strategy for patients with heart failure after myocarditis.