Metallothionein Prevents Diabetes-Induced Deficits in Cardiomyocytes by Inhibiting Reactive Oxygen Species Production

• Published in: Diabetes (New York, N.Y.) Vol. 52; no. 3; pp. 777 - 783
• Main Authors: Ye, Gang, Metreveli, Naira S, Ren, Jun, Epstein, Paul N
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01-03-2003
• Subjects: Angiotensin II - pharmacology; Angiotensin Receptor Antagonists; Animals; Biological and medical sciences; Calcium; Cardiomyocytes; Cardiomyopathy; Cardiovascular disease; Complications and side effects; Congestive heart failure; Development and progression; Diabetes; Diabetes Complications; Diabetes mellitus; Diabetes Mellitus - metabolism; Diabetes Mellitus - pathology; Diabetes therapy; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Gene Expression; Glucose; Glucose - pharmacology; Heart cells; Heart failure; Hypertension; Losartan - pharmacology; Mechanical properties; Metallothionein; Metallothionein - genetics; Metallothionein - physiology; Mice; Mice, Transgenic; Myocardial Contraction; Myocardium - metabolism; Myocardium - pathology; NADPH Oxidases - antagonists & inhibitors; Onium Compounds - pharmacology; Oxidative stress; Physiological aspects; Physiology; Reactive Oxygen Species - antagonists & inhibitors; Reactive Oxygen Species - metabolism; Receptor, Angiotensin, Type 1; Spectrometry, Fluorescence; Transgenic animals; United States
• DOI: 10.2337/diabetes.52.3.777
• EISSN: 1939-327X
• ISSN: 0012-1797

Metallothionein Prevents Diabetes-Induced Deficits in Cardiomyocytes by Inhibiting Reactive Oxygen Species Production
Gang Ye 1 ,
Naira S. Metreveli 1 ,
Jun Ren 2 and
Paul N. Epstein 1
1 Department of Pediatrics, University of Louisville School of Medicine, Louisville, Kentucky
2 Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota School of Medicine, Grand Forks, North
Dakota
Abstract
Many individuals with diabetes experience impaired cardiac contractility that cannot be explained by hypertension and atherosclerosis.
This cardiomyopathy may be due to either organ-based damage, such as fibrosis, or to direct damage to cardiomyocytes. Reactive
oxygen species (ROS) have been proposed to contribute to such damage. To address these hypotheses, we examined contractility,
Ca 2+ handling, and ROS levels in individual cardiomyocytes isolated from control hearts, diabetic OVE26 hearts, and diabetic hearts
overexpressing antioxidant protein metallothionein (MT). Our data showed that diabetic myocytes exhibited significantly reduced
peak shortening, prolonged duration of shortening/relengthening, and decreased maximal velocities of shortening/relengthening
as well as slowed intracellular Ca 2+ decay compared with control myocytes. Overexpressing MT prevented these defects induced by diabetes. In addition, high glucose
and angiotensin II promoted significantly increased generation of ROS in diabetic cardiomyocytes. Chronic overexpression of
MT or acute in vitro treatment with the flavoprotein inhibitor diphenyleneiodonium or the angiotensin II type I receptor antagonist
losartan eliminated excess ROS production in diabetic cardiomyocytes. These data show that diabetes induces damage at the
level of individual myocyte. Damage can be attributed to ROS production, and diabetes increases ROS production via angiotensin
II and flavoprotein enzyme‐dependent pathways.
Footnotes
Address correspondence and reprint requests to Paul N. Epstein, Department of Pediatrics, University of Louisville School
of Medicine, 570 S Preston St., Baxter Biomedical Building, Suite 304, Louisville, KY 40202. E-mail: paul.epstein{at}louisville.edu .
Received for publication 26 July 2002 and accepted in revised form 20 November 2002.
CM-H 2 DCFDA, 5-(6)-chloromethyl-2′, 7′-dichlorodihydrofluorescein diacetate; DPI, diphenyleneiodonium; FFI, fura2 fluorescence intensity;
KH, Krebs-Henseleit; MT, metallothionein; PS, peak shortening; ROS, reactive oxygen species; TPS 90 , time to 90% PS; TR 90 , time to 90% relengthening.
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