Abstract 4367371: Endogenous YAP Activation Promotes Myocardial Repair After Myocarditis by Suppressing IFN-γ/STAT1 Signaling

Abstract

Background: Adult mammalian hearts have limited regenerative capacity, yet most myocarditis patients experience natural healing. Activating intrinsic cardiac healing mechanisms is a promising regenerative medicine strategy. While forced Yes-associated protein 1 (YAP) expression drives cardiomyocyte proliferation and improves cardiac function in murine myocardial infarction, physiological roles of YAP in adult cardiomyocytes are largely unknown. Objective: This study investigated physiological role of YAP in cardiac remodeling during myocarditis and its molecular mechanisms underlying myocardial recovery. Methods and Results: In the murine experimental autoimmune myocarditis (EAM) model, inflammation causes cardiac dysfunction and myocardial injury at 3 weeks post-induction. By 5 weeks, cardiac function recovers due to tissue repair. Immunofluorescence staining revealed a significant increase in YAP nuclear localization in cardiomyocytes during inflammatory phase of EAM (0w;0.3±0.4%, 3w;15.1±5.3%, 5w;3.2±4.0%). We investigated YAP's involvement using cardiomyocyte-specific Yap1 -conditional knockout (YAPCKO) mice. In YAPCKO mice, EAM recovery was impaired (Δfractional shortening (3w-5w): Ctrl;7.1±5.4%, YAPCKO:1.0±2.3%), accompanied by histological changes: increased apoptotic cell death, fibrosis, reactive oxygen species production, reduced cardiomyocyte proliferation, and decreased capillary density. RNA-sequencing showed IFN-γ/STAT1 signaling activation in YAPCKO cardiomyocytes during myocarditis. Crucially, IFN-γ blockade with an anti-IFN-γ neutralizing antibody restored these 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-mediated SHP-2 induction suppressed STAT1 nuclear localization, reducing STAT1-mediated transcription both in vitro and in vivo . Conclusion: Endogenous YAP is a critical negative regulator of IFN-γ/STAT1 signaling, promoting myocardial repair post-myocarditis. Our findings provide novel molecular insights into myocardial healing and propose a new therapeutic strategy for heart failure patients after myocarditis.