Rosiglitazone Treatment in Zucker Diabetic Fatty Rats Is Associated With Ameliorated Cardiac Insulin Resistance and Protection From Ischemia/Reperfusion-Induced Myocardial Injury

Rosiglitazone Treatment in Zucker Diabetic Fatty Rats Is Associated With Ameliorated Cardiac Insulin Resistance and Protection From Ischemia/Reperfusion-Induced Myocardial Injury Tian-Li Yue , Weike Bao , Juan-Li Gu , Jianqi Cui , Ling Tao , Xin-Liang Ma , Eliot H. Ohlstein and Beat M. Jucker From the Department of Investigative and Cardiac Biology, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania Address correspondence and reprint requests to Tian-Li Yue, PhD, Department of Investigative and Cardiac Biology, GlaxoSmithKline, 709 Swedeland Rd., P.O. Box 1539, UW2510, King of Prussia, PA 19406. E-mail: tian-li_yue{at}gsk.com Abstract The mechanism responsible for the enhanced myocardial susceptibility to ischemic insult in patients with type 2 diabetes is not clear. The present study examines the effect of rosiglitazone treatment on cardiac insulin sensitization and its association with cardioprotection from ischemia/reperfusion injury in an animal model of diabetes. Male Zucker diabetic fatty (ZDF) rats were treated with rosiglitazone (3 mg · kg −1 · day −1 orally) or vehicle for 8 days before undergoing 30 min of coronary artery ligation, followed by reperfusion for 4 h (apoptosis) or 24 h (infarction). Rosiglitazone reduced the blood levels of glucose, triglycerides, and free fatty acids; enhanced cardiac glucose oxidation; and increased Akt phosphorylation (Akt-pS473) 2.1-fold and Akt kinase activity 1.8-fold in the ischemic myocardium. The phosphorylation of two downstream targets of Akt, glycogen synthase kinase-3β and FKHR (forkhead transcription factor), was also enhanced by 2- and 2.9-fold, respectively. In rosiglitazone-treated rats, the number of apoptotic cardiomyocytes and the myocardial infarct size were decreased by 58 and 46%, respectively, and the myocardial contractile dysfunction was improved. Blockade of the insulin-Akt signaling pathway by wortmannin in the 8-day rosiglitazone-treated ZDF rats resulted in a markedly diminished cardioprotective effect of rosiglitazone. In addition, 8-day rosiglitazone treatment in Zucker lean rats or 2-day rosiglitazone treatment in ZDF rats, both of which showed no change in whole-body insulin sensitivity, resulted in a significant reduction in cardiac infarct size, but to a lesser degree when compared with that observed in 8-day rosiglitazone–treated ZDF rats. These results suggest that chronic treatment with rosiglitazone protects the heart against ischemia/reperfusion injury in ZDF rats