Overexpression of Metallothionein Reduces Diabetic Cardiomyopathy

Q. Liang, E. C. Carlson, R. V. Donthi, P. M. Kralik, X. Shen, P. N. Epstein
2002 Diabetes  
Many diabetic patients suffer from cardiomyopathy, even in the absence of vascular disease. This diabetic cardiomyopathy predisposes patients to heart failure and mortality from myocardial infarction. Evidence from animal models suggests that reactive oxygen species play an important role in the development of diabetic cardiomyopathy. Our laboratory previously developed a transgenic mouse model with targeted overexpression of the antioxidant protein metallothionein (MT) in the heart. In this
more » ... e heart. In this study we used MT-transgenic mice to test whether an antioxidant protein can reduce cardiomyopathy in the OVE26 transgenic model of diabetes. OVE26 diabetic mice exhibited cardiomyopathy characterized by significantly altered mRNA expression, clear morphological abnormalities, and reduced contractility under ischemic conditions. Diabetic hearts appeared to be under oxidative stress because they had significantly elevated oxidized glutathione (GSSG). Diabetic mice with elevated cardiac MT (called OVE26MT mice) were obtained by crossing OVE26 transgenic mice with MT transgenic mice. Hyperglycemia in OVE26MT mice was indistinguishable from hyperglycemia in OVE26 mice. Despite this, the MT transgene significantly reduced cardiomyopathy in diabetic mice: OVE26MT hearts showed more normal levels of mRNA and GSSG. Typically, OVE26MT hearts were found to be morphologically normal, and elevated MT improved the impaired ischemic contractility seen in diabetic hearts. These results demonstrate that cardiomyocyte-specific expression of an antioxidant protein reduces damage to the diabetic heart. Diabetes 51:174 -181, 2002 RESEARCH DESIGN AND METHODS Animals. We have previously described the development of OVE26 diabetic mice (20). MT mice that overexpress MT 10-fold in the heart were also previously described (21). Transgenic mice of both lines were identified by the presence of phenotypic markers. OVE26-positive mice were recognized by the presence of small eyes caused by the cointegration of the GR19 gene (20) , which is expressed in the eye. MT-positive mice were recognized by the presence of coat color due to cointegration of the tyrosinase gene that corrects the mutant tyrosinase gene of FVB mice (22). All transgenic and nontransgenic animals were maintained on the inbred FVB background. Mice were maintained on a 12-h light/dark cycle and received food (Purina Laboratory Rodent Diet 5001) and water ad libitum. A U.S. Department of Agriculture-certified institutional animal care committee approved all animal procedures. From the
doi:10.2337/diabetes.51.1.174 pmid:11756338 fatcat:wvrndoytdvek7hnax5pauqeile