Trim65 attenuates isoproterenol-induced cardiac hypertrophy by promoting autophagy and ameliorating mitochondrial dysfunction via the Jak1/Stat1 signaling pathway

Pathological cardiac hypertrophy is a major cause of heart failure, and there is no effective approach for its prevention or treatment. The Trim family is a recently identified family of E3 ubiquitin ligases that regulate cardiac hypertrophy. Trim65, which is a memberof the Trim family, previous studies have not determined whether Trim65 affects cardiac hypertrophy. In this study, the effects of Trim65 on isoproterenol (ISO)-induced cardiac hypertrophy and the underlying mechanisms were investigated. In contrast to C57BL/6 mice, Trim65-knockout (Trim65-KO) mice developed more severe myocardial hypertrophy, fibrosis and cardiac dysfunction after being intraperitoneally injected with ISO for 2 weeks. Transmission electron microscopy (TEM) revealed that the autophagic flux was inhibited, mitochondria were swollen, and mitochondrial cristae were lost or decreased in the myocardium of Trim65-KO mice. In vitro studies demonstrated that overexpression of Trim65 inhibited ISO-induced cardiomyocyte hypertrophy by increasing mitochondrial density and membrane potential, and the STAT1 Inhibitor fludarabine attenuated the effect of Trim65 knockdown on ISO-induced cardiomyocyte hypertrophy by reducing Reactive Oxygen Species (ROS) production and increasing the mitochondrial density and membrane potential. Our findings provide the first link between Trim65 and mitochondria, and we found for the first time that Trim65 inhibits mitochondria-dependent Apoptosis and Autophagy via the JAK1/STAT1 signalling pathway, ultimately attenuating ISO-induced cardiac hypertrophy; this effect of Trim65 might be mediated via the regulation of JAK1 ubiquitination. Taking these findings together, we suggest that genes that are related to mitochondria-dependent Apoptosis and that are associated with Trim65 could be promising therapeutic targets for cardiac hypertrophy.

Autophagy; Cardiac hypertrophy; Isoproterenol; Mitochondria; Stat1; Trim65; Ubiquitination.