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Protection of Cardiac Mitochondria by Overexpression of MnSOD Reduces Diabetic Cardiomyopathy

¹ Department of Pathology, University of Washington, Seattle, Washington
² Department of Pediatrics, University of Louisville School of Medicine, Louisville, Kentucky

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 I, Suite 304, Louisville, KY 40202. E-mail: paul.epstein{at}louisville.edu

Abbreviations: DCFDA, 2'-7'-dichlorofluorescein diacetate; GSH, glutathione; MHC, myosin heavy chain; MnSOD, manganese superoxide dismutase; RCR, respiratory control ratio; ROS, reactive oxygen species; SOD, superoxide dismutase

We previously reported damage and elevated biogenesis in cardiac mitochondria of a type 1 diabetic mouse model and proposed that mitochondria are one of the major targets of oxidative stress. In this study, we targeted overexpression of the mitochondrial antioxidant protein manganese superoxide dismutase (MnSOD) to the heart to protect cardiac mitochondria from oxidative damage. Transgenic hearts had a 10- to 20-fold increase in superoxide dismutase (SOD) activity, and the transgenic SOD was located in mitochondria. The transgene caused a twofold increase in cardiac catalase activity. MnSOD transgenic mice demonstrated normal cardiac morphology, contractility, and mitochondria, and their cardiomyocytes were protected from exogenous oxidants. Crossing MnSOD transgenic mice with our type 1 model tested the benefit of eliminating mitochondrial reactive oxygen species. Overexpression of MnSOD improved respiration and normalized mass in diabetic mitochondria. MnSOD also protected the morphology of diabetic hearts and completely normalized contractility in diabetic cardiomyocytes. These results showed that elevating MnSOD provided extensive protection to diabetic mitochondria and provided overall protection to the diabetic heart.

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