Abstract 14374: Chronic Treatment with Rapamycin Attenuates Diabetes-Associated Adverse Effects and Protects Against Myocardial Ischemia/Reperfusion Injury in Type II Diabetic Mice
Background: Diabetes mellitus is a major risk factor for cardiovascular disease. The elevated mammalian target of rapamycin (mTOR) signaling contributes to the pathogenesis of diabetes. mTOR inhibition by Rapamycin (Sirolimus®, RAPA) is able to ameliorate diabetes-induced renal dysfunction and blocks the onset of type 1 diabetes. The purpose of the present study is to demonstrate the beneficial effect of chronic treatment with RAPA on the type 2 diabetic heart and to determine the mechanisms underlying this cardioprotection against ischemia/reperfusion (I/R) injury.
Methods and Results: Adult male db/db mice (n=20/group) were treated daily for 28 days with vehicle (5% DMSO, i.p.) or RAPA (0.25 mg/kg, i.p.). This treatment regimen significantly reduced body weight (33±1 gm vs 51±1 gm, p<0.0001), plasma glucose levels (436±22 mg/dL vs 557±23 mg/dL, p<0.005), triglycerides (60.4±3.5 mg/dL vs 92.5±13.2 mg/dL, p<0.05) and insulin (3.4±0.5 ng/ml vs 14.4±3.1 ng/ml, p<0.05) compared to control. Following treatment, the hearts were subjected to global I (20 min) and R (30 min) in Langendorff mode. RAPA significantly reduced infarct size (7.9±1.8 % vs 20±3.9 %, n=6, p<0.005) compared to vehicle. Ventricular myocytes were isolated from treated mice and subjected to 40 min simulated ischemia. Necrosis was determined by trypan blue exclusion after 1 hr of reoxygenation (RO) and apoptosis was assessed by TUNEL after 18 hr of RO. RAPA significantly reduced necrosis as compared to vehicle (28.6±1.2% vs 45.8±2.2%) and apoptosis (9.8±0.9% vs 23.2 ±0.3%) (n=4, p<0.0005). Furthermore, RAPA reduced phosphorylation of mTOR, but induced plasma IL-6 level (1958±726 vs 176.4±17 A.U. p<0.05) compared to vehicle and phosphorylation of its downstream target STAT3 (Fig 1A), in concert with miRNA-17 and 20a in db/db mice (Fig 1B).
Conclusion: RAPA protects type 2 diabetic heart against I/R injury through IL-6-STAT3-miR-17/20a pathway.
- © 2011 by American Heart Association, Inc.