Abstract 13300: Rapamycin Causes miRNA-20a Mediated Suppression of Egln3/prolylhydroxylase-3 and Protects against Ischemia/Reperfusion Injury in Type II Diabetic Heart
Background: Excessive activation of the mammalian target of rapamycin (mTOR) is implicated in diabetic complications and is associated with higher risk of congestive heart failure. Previous studies reported that chronic treatment with rapamycin, mTOR inhibitor, improved cardiac function and reduced infarct size after myocardial infarction and also ameliorated diabetes-induced renal dysfunction. Recent evidence showed decreased levels of activated STAT3 in diabetic heart, and its downstream target, miRNA-20a, inhibits stress-induced cardiomyocyte apoptosis by down-regulating Egln3/prolyl hydroxylase. Therefore, we tested the hypothesis that the cardioprotective effect of chronic treatment with rapamycin against ischemia/reperfusion (I/R) injury in the diabetic heart is mediated through STAT3-miRNA-20 pathway.
Methods and Results: Adult male wild type or db/db mice were treated daily for 28 days with vehicle (5% DMSO, i.p.) or rapamycin (0.25 mg/kg, i.p.). We observed a significant reduction in body weight, fasting plasma glucose levels, triglyceride and insulin following rapamycin treatment compared to vehicle. Rapamycin reduced infarct size compared to vehicle following I/R and also reduced necrosis and apoptosis following simulated ischemia/reoxygenation in adult cardiomyocytes isolated from treated db/db mice. The plasma level of IL-6 and phosphorylation of STAT3 were increased in rapamycin-treated db/db mice. MicroRNA microarray and real time PCR revealed that microRNA-20a and -17, part of miRNA-17-92 cluster, were significantly induced in heart and cardiomyocytes of rapamycin-treated db/db mice (Fig A,B). Moreover, significant reduction of the transcript level and expression of pro-apoptotic prolyl hydroxylase protein Egln3/PHD3 were observed (Fig.C,D).
Conclusion: Our results suggest that rapamycin causes miRNA-20a-mediated suppression of Egln3/PHD3 that may be associated with cardioprotection in type II diabetic mice.
- © 2012 by American Heart Association, Inc.