Abstract 14020: Chronic Rapamycin Treatment Improves Cardiac Function by Attenuating Oxidative Stress and Altering Contractile Proteins in Type 2 Diabetic Mice
Background: Elevated mTOR (mammalian target of rapamycin) signaling contributes to the pathogenesis of diabetes, with increased morbidity and mortality, mainly due to cardiovascular complications. Since mTOR inhibition with rapamycin is protective against ischemia/reperfusion injury, we hypothesized that rapamycin would improve cardiac function in type 2 diabetes (T2D). In addition, we investigated the possible mechanisms and novel protein targets involved in rapamcyin-induced improvement of cardiac function in T2D mice.
Methods and Results: Adult male leptin receptor null, homozygous db/db or wild type mice were treated daily for 28 days with vehicle (5% DMSO, i.p.) or rapamycin (0.25 mg/kg, i.p.). Cardiac function was monitored by echocardiography and protein targets were identified by proteomics. Rapamycin treatment significantly reduced body weight, fasting plasma glucose, triglyceride and insulin levels in db/db mice. Fractional shortening (FS) was improved by rapamycin treatment (45.7±2.5% vs 35.8±2.7 % in control, p<0.05). Oxidative stress as evidenced by glutathione levels and lipid peroxidation was significantly reduced following rapamycin treatment in db/db hearts. In addition, rapamycin blocked phosphorylation of mTOR and S6, while AKT phosphorylation was not. Proteomic analysis by 2D-gel identified 30 protein spots that were significantly altered in db/db mice treated with rapamycin. Mass spectrometric and western blot analyses identified significant changes in the cytoskeletal/contractile proteins (myosin light chain MLY2, myosin heavy chain 6, ferritin heavy chain 1), glucose metabolism proteins (pyruvate dehydrogenase E1, PYGB) and antioxidant protein (peroxiredoxin 5) following rapamycin treatment (Figure)
Conclusion: Chronic rapamycin treatment improves cardiac function in T2D mice, possibly through attenuation of oxidative stress and the change of antioxidant and contractile protein expression.
- © 2013 by American Heart Association, Inc.