Strip1 Is a Novel Negative Regulator of Cardiomyocyte Hypertrophy.

Abstract

Pathological cardiac hypertrophy is a critical factor leading to cardiomyopathy and ultimately heart failure. While several signaling pathways controlling cardiac hypertrophy have been identified, the molecular mechanisms underlying their precise regulation remain incompletely understood. Strip1, a structural component of STRIPAK complexes, has been implicated in various cellular functions; however, its role in cardiomyocytes is uncharacterized. Here we identify Strip1 as a potent anti-hypertrophic factor, controlling cell size and the hypertrophic gene program in neonatal rat ventricular cardiomyocytes (NRVCMs). STRIP1 expression was found to be significantly reduced in human dilated and ischemic cardiomyopathies (DCM/ICM), as well as in murine stress model induced by transverse aortic constriction (TAC). In a knockdown model with morpholino-driven STRIP1 reduction in zebrafish in vivo, impaired cardiac function and heart failure-like features were observed. Interestingly, Strip1 localized to the nucleolus in NRVCMs, suggesting a putative nuclear/epigenetic role in cardiomyocytes. Furthermore, our data support association of Strip1 with cardiac STRIPAK complex, modulating kinase activities, including MST1/MST2 and MST4. Mechanistically, Strip1 appears to influence prohypertrophic signaling, including Hippo- and Calcineurin/NFAT-related pathways, which may contribute to pathological cardiac remodeling. Collectively, these findings establish Strip1 as an important modulator of cardiomyocyte hypertrophy and a potential therapeutic target for cardiomyopathy and heart failure.