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.

改变的自噬与几种人类心血管疾病有关。远程缺血调理 (RIC) 在多种心血管损伤模型中具有心脏保护作用并改变自噬信号传导，但尚未报道其在基因操作诱导的心肌病中的作用。研究Atg5敲低导致自噬长期减少对心脏的影响，并评估 RIC 是否可以挽救该表型。在心脏特异性条件Atg5中用他莫昔芬诱导Atg5敲低 14 天弗洛克斯老鼠。分别通过蛋白质印迹和超声心动图评估自噬蛋白和心脏功能。RIC 是通过使用止血带的周期性后肢缺血和再灌注诱导的。在他莫昔芬诱导期间每天进行 RIC 或假手术，并且在单独的实验中，长期每周 3 次，持续 8 周。在研究结束时评估心脏反应。Atg5的心脏特异性敲低蛋白质水平降低了 70%，并与 mTOR 的显着增加、LC3-II 的减少和上游自噬蛋白（包括 LC3-I、P62 和 Beclin）的增加有关。在 17 个月的随访期间，生化标志物的变化与年龄相关性心肌病的发展有关，表现为心脏重量体重比增加、心功能进行性下降和过早死亡。RIC 增加心脏 ATG5 并挽救了一些Atg5敲低诱导的心肌病表型和相关的形态学重塑。我们得出结论，心脏特异性Atg5敲低导致与年龄相关的心肌病的发展。RIC 在急性和长期给药时会逆转分子和结构表型。