Overexpression of Metallothionein Reduces Diabetic Cardiomyopathy

• Published in: Diabetes (New York, N.Y.) Vol. 51; no. 1; pp. 174 - 181
• Main Authors: QIANGRONG LIANG, CARLSON, Edward C, DONTHI, Rajakumar V, KRALIK, Patrica M, XIA SHEN, EPSTEIN, Paul N
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.01.2002
• Subjects: Actins - genetics; Animals; Antioxidants; Antioxidants - metabolism; Atrial Natriuretic Factor - genetics; Base Sequence; Biological and medical sciences; Blood Glucose - metabolism; Blotting, Northern; Cardiomyopathies - physiopathology; Cardiomyopathies - prevention & control; Cardiomyopathy; Cardiovascular disease; Care and treatment; Complications; Coronary vessels; Diabetes; Diabetes mellitus; Diabetic Angiopathies - physiopathology; Diabetic Angiopathies - prevention & control; Disease Models, Animal; Gene Expression Regulation - physiology; Genes; Glucose; Glutathione Disulfide - metabolism; Heart attacks; Heart failure; Hyperglycemia; Insulin; Insulin - blood; Ischemia; Kinases; Metallothionein; Metallothionein - genetics; Mice; Mice, Transgenic; Molecular Sequence Data; Morphology; Myocardial Contraction - physiology; Myocardial diseases; Oligonucleotide Probes; Oxidative stress; Physiological aspects; Proteins; Risk factors; RNA, Messenger - genetics; Transcription, Genetic; Transgenic animals; Triglycerides - blood; Vein & artery diseases; United States
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.51.1.174

Overexpression of Metallothionein Reduces Diabetic Cardiomyopathy Qiangrong Liang 1 , Edward C. Carlson 2 , Rajakumar V. Donthi 3 , Patrica M. Kralik 3 , Xia Shen 3 and Paul N. Epstein 3 1 Division of Molecular Cardiovascular Biology, University of Cincinnati, Ohio 2 Department of Anatomy and Cell Biology, University of North Dakota, Grand Forks, North Dakota 3 Department of Pediatrics, University of Louisville, Louisville, Kentucky Abstract 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 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. Footnotes Address correspondence and reprint requests to Paul N. Epstein, Department of Pediatrics, University of Louisville, Baxter Research Building, Suite 321, Louisville, KY 40202. E-mail: paul.epstein{at}louisville.edu . Received for publication 23 March 2001 and accepted in revised form 19 October 2001. ANF, atrial natriuretic factor; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GSH, glutathione; GSSG, oxidized GSH; M2VP, 1-methyl-2-vinyl-pyridinium trifluoromethane sulfonate; MT, metallothionein; ROS, reactive oxygen species.