Catalase Protects Cardiomyocyte Function in Models of Type 1 and Type 2 Diabetes

Catalase Protects Cardiomyocyte Function in Models of Type 1 and Type 2 Diabetes Gang Ye 1 , Naira S. Metreveli 1 , Rajakumar V. Donthi 1 , Shen Xia 1 , Ming Xu 1 , Edward C. Carlson 2 and Paul N. Epstein 1 1 Department of Pediatrics, University of Louisville School of Medicine, Louisville, Kentucky 2 Department of Anatomy and Cell Biology, University of North Dakota, Grand Forks, North Dakota Address correspondence and reprint requests to Paul N. Epstein, PhD, Department of Pediatrics, University of Louisville School of Medicine, 570 S. Preston St., Baxter Biomedical Building, Suite 304, Louisville, KY 40202. E-mail: paul.epstein{at}louisville.edu Abstract Many diabetic patients suffer from a cardiomyopathy that cannot be explained by poor coronary perfusion. Reactive oxygen species (ROS) have been proposed to contribute to this cardiomyopathy. Consistent with this we found evidence for induction of the antioxidant genes for catalase in diabetic OVE26 hearts. To determine whether increased antioxidant protection could reduce diabetic cardiomyopathy, we assessed cardiac morphology and contractility, Ca 2+ handling, malondialdehyde (MDA)-modified proteins, and ROS levels in individual cardiomyocytes isolated from control hearts, OVE26 diabetic hearts, and diabetic hearts overexpressing the antioxidant protein catalase. Diabetic hearts showed damaged mitochondria and myofibrils, reduced myocyte contractility, slowed intracellular Ca 2+ decay, and increased MDA-modified proteins compared with control myocytes. Overexpressing catalase preserved normal cardiac morphology, prevented the contractile defects, and reduced MDA protein modification but did not reverse the slowed Ca 2+ decay induced by diabetes. Additionally, high glucose promoted significantly increased generation of ROS in diabetic cardiomyocytes. Chronic overexpression of catalase or acute in vitro treatment with rotenone, an inhibitor of mitochondrial complex I, or thenoyltrifluoroacetone, an inhibitor of mitochondrial complex II, eliminated excess ROS production in diabetic cardiomyocytes. The structural damage to diabetic mitochondria and the efficacy of mitochondrial inhibitors in reducing ROS suggest that mitochondria are a source of oxidative damage in diabetic cardiomyocytes. We also found that catalase overexpression protected cardiomyocyte contractility in the agouti model of type 2 diabetes. These data show that both type 1 and type 2 diabetes induce damage at the level of individual myoc