Many diabetics suffer from a severe cardiomyopathy even in the absence of vascular disease. This diabetic cardiomyopathy may predispose diabetics to heart failure and mortality from myocardial infarction. Evidence from animal models suggests that oxygen free radicals play an important role in the development of diabetic cardiomyopathy. Our laboratory has developed transgenic mouse models that are protected from cardiac free radical damage by targeted overexpression of the scavengers, catalase and metallothionein (MT) in the heart. We are also developing a transgenic model that overexpresses the scavenger manganese super oxide dismutase in the heart. This proposal will utilize these transgenic mice to test the hypotheses that free radical damage contributes to diabetic cardiomyopathy and that increased expression of free radical scavengers will protect the heart from diabetic cardiomyopathy. Transgenic mice protected from cardiac free radicals will be crossed to a transgenic model of severe, prolonged and early onset diabetes that we have found to display morphological features of diabetic cardiomyopathy. Diabetic mice carrying the free radical protective transgenes will be compared to unprotected diabetic mice for signs of cardiomyopathy. Hearts will be analyzed for differences in morphology, contractility, sensitivity to ischemia and indices of free radical damage. These results will provide strong evidence on the role of free radicals in diabetic cardiomyopathy and they will demonstrate the potential of antioxidant therapy. Our initial results indicate that overexpression of MT provides dramatic protection from the morphological damage of diabetic cardiomyopathy.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Metabolism Study Section (MET)
Program Officer
Linder, Barbara
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Dakota
Schools of Medicine
Grand Forks
United States
Zip Code
Wang, Qianwen; Donthi, Rajakumar V; Wang, Jianxun et al. (2008) Cardiac phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase increases glycolysis, hypertrophy, and myocyte resistance to hypoxia. Am J Physiol Heart Circ Physiol 294:H2889-97
Shen, Xia; Zheng, Shirong; Metreveli, Naira S et al. (2006) Protection of cardiac mitochondria by overexpression of MnSOD reduces diabetic cardiomyopathy. Diabetes 55:798-805
Ye, Gang; Donthi, Rajakumar V; Metreveli, Naira S et al. (2005) Overexpression of hexokinase protects hypoxic and diabetic cardiomyocytes by increasing ATP generation. Cardiovasc Toxicol 5:293-300
Donthi, Rajakumar V; Ye, Gang; Wu, Chaodong et al. (2004) Cardiac expression of kinase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase inhibits glycolysis, promotes hypertrophy, impairs myocyte function, and reduces insulin sensitivity. J Biol Chem 279:48085-90
Ye, Gang; Metreveli, Naira S; Donthi, Rajakumar V et al. (2004) Catalase protects cardiomyocyte function in models of type 1 and type 2 diabetes. Diabetes 53:1336-43
Zheng, Shirong; Noonan, William T; Metreveli, Naira S et al. (2004) Development of late-stage diabetic nephropathy in OVE26 diabetic mice. Diabetes 53:3248-57
Ye, Gang; Metreveli, Naira S; Ren, Jun et al. (2003) Metallothionein prevents diabetes-induced deficits in cardiomyocytes by inhibiting reactive oxygen species production. Diabetes 52:777-83
Carlson, Edward C; Audette, Janice L; Veitenheimer, Nicole J et al. (2003) Ultrastructural morphometry of capillary basement membrane thickness in normal and transgenic diabetic mice. Anat Rec A Discov Mol Cell Evol Biol 271:332-41
Duan, Jinhong; Zhang, Hai-Ying; Adkins, Steven D et al. (2003) Impaired cardiac function and IGF-I response in myocytes from calmodulin-diabetic mice: role of Akt and RhoA. Am J Physiol Endocrinol Metab 284:E366-76
Liang, Qiangrong; Donthi, Rajakumar V; Kralik, Patricia M et al. (2002) Elevated hexokinase increases cardiac glycolysis in transgenic mice. Cardiovasc Res 53:423-30

Showing the most recent 10 out of 13 publications