Ischemic post-conditioning (IPO) activates Akt signaling to confer cardioprotection. The responsiveness of diabetic hearts to IPO is impaired. We hypothesized that decreased cardiac SIRT1, a positive regulator of Akt, may be responsible for the impaired responsiveness of diabetic hearts to IPO-mediated cardioprotection. High-fat diet and streptozotocin-induced diabetic mice were subjected to myocardial ischemia/reperfusion (MI/R, 30 minutes ischemia and 180 minutes reperfusion) or IPO (three cycles of 10 s of reperfusion and ischemia at the onset of reperfusion). Adenoviral vectors encoding GFP or SIRT1 (Ad-SIRT1) were administered by direct injection into the left ventricular. IPO activated the Akt signaling pathway and reduced MI/R injury in nondiabetic hearts but not in diabetic hearts, in which reduced expression of SIRT1 and increased Akt acetylation were observed. Delivery of Ad-SIRT1 into the diabetic hearts reduced Akt acetylation and restored the cardioprotective effects of IPO. In in vitro study, transfection with wild type SIRT1 but not inactive mutant SIRT1 reduced the expression of Akt acetylation and restored the protective effects of hypoxic post-conditioning in high glucose-incubated primary cardiomyocytes. Moreover, the cardiomyocytes transfected with Akt acetylation-defective mutant (K20R) showed increased Akt phosphorylation and enhanced protective effects against hypoxia/reoxygenation injury. These findings demonstrate that SIRT1 up-regulation restores IPO-mediated cardioprotection in diabetic mice via deacetylation-dependent activation of Akt signaling pathway. It is suggested that targeting up-regulation of SIRT1 may be a potential therapeutic strategy to restore myocardial responsiveness to post-conditioning in diabetic patients.
M. Ding: None. K. Zeng: None. M. Yu: None. C. Liu: None. F. Fu: None.
National Natural Science Foundation of China (81600235, 81670354); Natural Science Foundation of Shaanxi (2018JM7061)