SNX3 aggravates pathological cardiac hypertrophy via targeting ATG5-dependent autophagy

Abstract Autophagy is an intracellular lysosomal degradation pathway that plays a critical role in maintaining cardiac homeostasis. Disordered autophagy is closely related to the pathological process of many heart diseases, including cardiac hypertrophy. However, mechanisms regulating cardiac autophagy remained unclear. Previously, we found that overexpression of SNX3 induces cardiac hypertrophy in mice. In this study, a reduced autophagy was observed in SNX3 transgenic mice. Therefore, the objective of our study was to determine whether SNX3 regulates pathological cardiac hypertrophy by regulating autophagy process. A decreased level of autophagy-related protein LC3 was detected in failing hearts from human patients and mouse models. To explore the role of SNX3 in cardiac autophagy, we generated cardiac-specific SNX3 transgenic mice and infected neonatal rat cardiomyocytes (NRCMs) with adenovirus encoding SNX3 (Ad-SNX3). Both in vivo and in vitro studies suggested that overexpression of SNX3 inhibited cardiomyocytes autophagy. Overexpression of SNX3 in vitro further reduced ISO-induced autophagic flux through inhibiting autophagic formation. Rapamycin, an autophagy inducer, could effectively reversed SNX3-induced cardiac hypertrophy and autophagy inhibition both in vitro and in vivo. Immunofluorescent staining and co-immunoprecipitation results revealed an interaction between SNX3 and autophagy related gene 5 (ATG5). We discovered that the stability of ATG5 was impaired by SNX3.