Atg5 knockdown induces age-dependent cardiomyopathy which can be rescued by repeated remote ischemic conditioning

Wang, Fangfei; He, Quan; Gao, Zhiqian; Redington, Andrew N.

Altered autophagy is implicated in several human cardiovascular diseases. Remote ischemic conditioning (RIC) is cardioprotective in multiple cardiovascular injury models and modifies autophagy signaling, but its effect in cardiomyopathy induced by gene manipulation has not been reported. To investigate the cardiac effects of chronically reduced autophagy as a result of Atg5 knockdown and assess whether RIC can rescue the phenotype. Atg5 knockdown was induced with tamoxifen for 14 days in cardiac-specific conditional Atg5 flox mice. Autophagy proteins and cardiac function were evaluated by Western blot and echocardiography, respectively. RIC was induced by cyclical hindlimb ischemia and reperfusion using a tourniquet. RIC or sham procedure was performed daily during tamoxifen induction and, in separate experiments, chronically 3 times per week for 8 weeks. Cardiac responses were assessed by end of the study. Cardiac-specific knockdown of Atg5 reduced protein levels by 70% and was associated with a significant increase in mTOR, a reduction of LC3-II and increased upstream autophagy proteins including LC3-I, P62, and Beclin. The changes in biochemical markers were associated with development of an age-related cardiomyopathy during the 17-month follow-up indicated by increased heart weight body weight ratio, progressive decline in cardiac function, and premature death. RIC increased cardiac ATG5 and rescued some of the Atg5 knockdown-induced cardiomyopathy phenotype and associated morphological remodeling. We conclude that cardiac-specific Atg5 knockdown leads to the development of age-related cardiomyopathy. RIC reverses the molecular and structural phenotype when administered both acutely and chronically. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00395-021-00888-2.