Repeated remote ischemic preconditioning enhances post‐ischemic myocardial STAT5A and STAT3 but not STAT5B to confer cardioprotection in diabetic rats

Abstract

Background Remote ischemic preconditioning (RIPC) protects the hearts from ischemia/reperfusion (I/R) injury experimentally. In patients undergoing cardiac surgery, RIPC exhibits cardioprotection, while in studies that included diabetic patients, RIPC lost effectiveness in cardioprotection. In order to confer cardioprotection in diabetes, the threshold for RIPC has to be increased. In diabetic rats, repeated RIPC (rRIPC) for three days reduces myocardial infarction. In a recent study that included diabetic patients, rRIPC conferred beneficial effects (Balin M. et al. Cardiovasc Ther. 2019; doi: 10.1155/2019/9592378), but the mechanism is unclear. RIPC when applied well in advance of cardiac surgery conferred cardioptection that was associated increases of both cardiac STAT3 and STAT5. We hypothesized that both STAT5A and STAT5B are needed for rRIPC cardioprotection. Methods Eight‐week STZ‐induced diabetic rats received rRIPC (three episodes of 5 min occlusion of the left femoral artery followed by 5 min of reperfusion for 3 consecutive days) before being subjected to myocardial I/R (30 minutes of coronary artery ligation and 2 hours of reperfusion). In vitro, cardiac myoblast H9c2 cell hypoxia/reoxygenation (H/R) injury model was established with 6 hours of hypoxia followed by 12 hours of normoxia reoxygenation. The cells in the conditioning group were exposed to 3 cycles of 10 minutes of alternating nitrogen‐flushed hypoxia and reoxygenation as stimulated RIPC (sRIPC) 24 hours before inducing prolonged H/R. Results rRIPC reduced post‐ischemic myocardial infarct size and apoptotic cardiomyocyte death in diabetic rats (p <0.05) that was concomitant with significantly increases of myocardial p‐STAT3, p‐STAT5A, but not p‐STAT5B. In cultured H9C2 cells, sRIPC significantly attenuated the H/R‐induced increases in LDH release and the reduction in cell viability (all p<0.05, sRIPC+H/R vs. H/R). However, sRIPC mediated cellular protection was cancelled respectively by the Janus Kinase 2 Inhibitor AG490, by gene knock‐down of either STAT3 or STAT5A, but not by STAT5B gene knockdown. Conclusions Our findings suggest that STAT5A and STAT3 but not STAT5B are critical for repeated RIPC to confer cardioprotection. Support or Funding Information This study is supported by Health and Medical Research Fund (05161826) and NSFC grants(81770824 and 81670770)