Tspan9 Exacerbates Cardiac Hypertrophy by Impairing Cardiac Autophagy

ABSTRACT Pathological cardiac hypertrophy leads to heart failure. In this study, we aimed to explore the role of transmembrane protein Tspan9 in the development of cardiac hypertrophy and failure. We found that Tspan9 was upregulated in the hearts of patients with hypertrophic cardiomyopathy (HCM), in the hearts of mice subjected to transverse aortic constriction (TAC), as well as in phenylephrine‐induced hypertrophic neonatal rat cardiomyocytes (NRCMs). AAV9‐mediated overexpression (OE) of Tspan9 in mouse hearts augmented TAC‐induced cardiac hypertrophy and failure, while Tspan9 knockdown (KD) alleviated this effect. Tspan9‐OE promotes PE‐induced cardiomyocyte enlargement, whereas Tspan9‐KD suppresses it. Mechanistically, we demonstrated that Tspan9 interacts with p62, a pivotal regulator of autophagy, impairs its cargo function, leading to autophagy suppression. Remarkably, the anti‐hypertrophic effect of Tspan9‐KD was impaired when autophagy was inactivated or p62 was knocked down. These findings suggest that Tspan9 exacerbates pressure overload‐induced pathological cardiac hypertrophy and failure by suppressing cardiac autophagy through its interaction with p62.