STAT3-miR-17/20 Signaling Axis Plays a Critical Role in Attenuating Myocardial Infarction following Rapamycin Treatment in Diabetic mice.

AIMS Deregulation of mTOR (mammalian target of rapamycin) signaling occurs in diabetes, which exacerbates injury following myocardial infarction. We therefore investigated the infarct-limiting effect of chronic treatment with rapamycin (RAPA, mTOR inhibitor) in diabetic mice following myocardial ischemia/reperfusion (I/R) injury and delineated the potential protective mechanism. METHODS AND RESULTS Adult male diabetic (db/db) or wild type (C57) mice were treated with RAPA (0.25 mg/kg/day, intraperitoneal) or vehicle (5% DMSO) for 28 days. The hearts from treated mice were subjected to global I/R in Langendorff mode. Cardiomyocytes, isolated from treated mice, were subjected to simulated ischemia/reoxygenation (SI/RO) to assess necrosis and apoptosis. Myocardial infarct size was increased in diabetic heart following I/R as compared to wild type. Likewise, enhanced necrosis and apoptosis were observed in isolated cardiomyocytes of diabetic mice following SI/RO. Treatment with RAPA reduced infarct size as well as cardiomyocyte necrosis and apoptosis of diabetes and wild type mice. RAPA increased STAT3 phosphorylation and miRNA-17/20a expression in diabetic hearts. In addition, RAPA restored AKT phosphorylation (target of mTORC2), but suppressed S6 phosphorylation (target of mTORC1) following I/R injury. RAPA-induced cardioprotection against I/R injury as well as the induction of miR-17/20a and AKT phosphorylation were abolished in cardiac-specific STAT3-deficient diabetic mice, without alteration of S6 phosphorylation. The infarct-limiting effect of RAPA was obliterated in cardiac-specific miRNA-17-92-deficient diabetic mice. The post-I/R restoration of phosphorylation of STAT3 and AKT with RAPA were also abolished in miRNA-17-92-deficient diabetic mice. Additionally, RAPA suppressed the pro-apoptotic prolyl hydroxylase (Egln3/PHD3), a target of miRNA-17/20a in diabetic hearts, which was abrogated in miRNA-17-92-deficient diabetic mice. CONCLUSION Induction of STAT3-miRNA-17-92 signaling axis plays a critical role in attenuating myocardial infarction in RAPA-treated diabetic mice. Our study indicates that chronic treatment with RAPA might be a promising pharmacological intervention for attenuating myocardial infarction and improving prognosis in diabetic patients. CLINICAL PERSPECTIVE The prevalence of heart disease and associated cardiovascular complications are a major cause of morbidity and mortality in diabetics. This study provides a novel mechanism by which mTOR inhibition with chronic low-dose RAPA treatment induces protective effect against acute MI in diabetic mice. Specifically, the results show an essential role of a highly innovative STAT3-miR-17-92-mTOR signaling axis in cardioprotection in diabetes, which may have potential clinical relevance in preventing I/R injury in diabetics because RAPA has relatively mild side effects at low dose. Future studies using cardiac tissue from diabetic and non-diabetic patients undergoing elective cardiac surgery may further confirm the role of this signaling pathway in the context of myocardial I/R injury.