STAT3-miR-17/20 Signaling Axis Plays a Critical Role in Attenuating Myocardial Infarction Following Rapamycin Treatment in Diabetic Mice – DocWire…

AIMS:

Deregulation of mTOR (mammalian target of rapamycin) signaling occurs in diabetes, which exacerbates injury followingmyocardial infarction. We therefore investigated the infarct-limiting effect of chronic treatment with rapamycin (RAPA, mTOR inhibitor) in diabetic mice followingmyocardialischemia/reperfusion (I/R) injury and delineated the potential protective mechanism.

Adult male diabetic (db/db) or wild type (C57) mice were treated with RAPA (0.25mg/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.Myocardialinfarct 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.

Induction of STAT3-miRNA-17-92 signaling axis plays a critical role in attenuatingmyocardial infarctionin RAPA-treated diabetic mice. Our study indicates that chronic treatment with RAPA might be a promising pharmacological intervention for attenuatingmyocardial infarctionand improving prognosis in diabetic patients.

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 ofmyocardialI/R injury.

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