Abstract

Many diabetics suffer from severe cardiomyopathy even in the absence of vascular disease. Evidence from animal models and clinical samples implicate reactive oxygen species (ROS) in the development of diabetic cardiomyopathy. Our results confirm the importance of ROS. In the OVE26 model of Type I diabetes we find increased cardiac oxidative damage, increased production of ROS by diabetic cardiomyocytes and protection by antioxidant transgenes. Two different antioxidant proteins targeted to the cardiomyocyte, metallothionein (MT) and catalase prevented most of the primary characteristics of diabetic cardiomyopathy, including reduced contractility, impaired calcium homeostasis and disrupted morphology. Our most recent data implicate mitochondrial electron transport and the enzyme NADPH oxidase in the production of oxidative damage in diabetic cardiomyocytes. This project will identify the cellular source of increased ROS production in diabetic hearts, determine which proteins are the targets of ROS modification and test whether the importance of ROS in Type I diabetes also applies to cardiomyopathy in Type II diabetes. Sources of ROS will be tested by measuring ROS production in diabetic cardiomyocytes as a function of genetic knockout or drug inhibition of potential sources. Breeding diabetic mice to knockout mice for NADPH oxidase will determine if this enzyme is required for the development of diabetic cardiomyopathy. Protein targets of ROS modification in whole heart, mitochondria and sarcoplasmic reticulum will be identified by using proteomic analysis combined with antibodies against oxidatively modified amino acids. To analyze the role of ROS in Type II diabetic cardiomyopathy we will characterize cardiac morphology, ROS production, cardiac function and oxidative damage in the agouti model of Type II diabetes. Agouti mice will be bred to mice protected by cardiac specific antioxidant transgenes to determine if oxidative damage is a requirement for cardiomyopathy in this model.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL062892-07
Application #
6892143
Study Section
Metabolism Study Section (MET)
Program Officer
Varghese, Jamie
Project Start
1999-08-01
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
7
Fiscal Year
2005
Total Cost
$294,000
Indirect Cost

  Institution

Name
University of Louisville
Department
Pediatrics
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292

  Publications

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
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
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
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