Catalase alleviates cardiornyocyte dysfunction in diabetes: role of Akt, Forkhead transcriptional factor and silent information regulator 2

Oxidative stress has been speculated to play an essential role in diabetic cardiomyopathy. This study was designed to examine the effect of the antioxidant catalase on diabetes-induced cardiomyocyte dysfunction and the cellular mechanisms involved. Adult wild-type (FVB) and transgenic mice with cardiac-specific overexpression of catalase were made diabetic by a single injection of streptozotocin (STZ, 220 mg/kg; i.p., maintained for two weeks). Cardiomyocyte contractile properties were evaluated including peak shortening (PS), time-to-PS (TPS), time-to-relengthening (TR90), maximal velocity of shortening/relengthening (+/- dL/dt), intracellular Ca2+ level and decay rate. STZ depressed -dL/dt, prolonged TPS and TR90, elevated resting intracellular Ca2+ level and reduced intracellular Ca2+ decay in FVB myocytes. While catalase exhibited little effect on contractile and intracellular Ca2+ properties in control myocytes, it negated diabetes-induced cardiomyocyte mechanical abnormalities. Diabetic myocytes exhibited enhanced levels of reactive oxygen species and apoptosis, which were alleviated by catalase. Western blot analysis revealed that diabetes reduced Akt phosphorylation, enhanced the silent information regulator 2 (Sirt2), and upregulated Forkhead transcriptional factor Foxo3a as well as glycogen synthase kinase-3 beta (GSK-3 beta) and pGSK-3 beta. While catalase itself exhibited little effect on these proteins or their phospborylation (with the exception of Sirt2), it significantly attenuated diabetes-induced alteration in pAkt, Foxo3a and Sirt2 without affecting GSK-3 beta. Inhibition of Sirt2 using splitomicin impaired cardiomyocyte contractile function (reduced PS, +/- dL/dt, prolonged TPS and TR90). In summary, our data suggest potential roles of Akt, Foxo3a and Sirt2 in the onset of diabetic cardiomyopathy and the therapeutic potential of catalase. (C) 2007 Elsevier Inc. All rights reserved.