Published online before print March 5, 2007, doi: 10.1161/CIRCULATIONAHA.106.666941
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(Circulation. 2007;115:1408-1416.)
© 2007 American Heart Association, Inc.
Molecular Cardiology |
Adiponectin Cardioprotection After Myocardial Ischemia/Reperfusion Involves the Reduction of Oxidative/Nitrative Stress
From the Department of Emergency Medicine (L.T., X.J., Y.Y., S.L., T.A.C., B.L.P., X.L.M.), Center for Translational Medicine (E.G., W.K.), and Division of Endocrinology, Diabetes, and Metabolic Diseases (B.J.G.), Thomas Jefferson University, Philadelphia, Pa; and Section of Diabetes, Endocrinology, and Metabolism (L.C.), Department of Medicine, Baylor College of Medicine, Houston, Tex.
Correspondence to Dr Xin L. Ma, MD, PhD, Department of Emergency Medicine, 1020 Sansom St, Thompson Bldg, Rm 241, Philadelphia, PA 19107. E-mail xin.ma{at}jefferson.edu
Received September 26, 2006; accepted January 5, 2007.
Background— Several clinical studies have demonstrated that levels of adiponectin are significantly reduced in patients with type 2 diabetes and that adiponectin levels are inversely related to the risk of myocardial ischemia. The present study was designed to determine the mechanism by which adiponectin exerts its protective effects against myocardial ischemia/reperfusion.
Methods and Results— Adiponectin–/– or wild-type mice were subjected to 30 minutes of myocardial ischemia followed by 3 hours or 24 hours (infarct size and cardiac function) of reperfusion. Myocardial infarct size and apoptosis, production of peroxynitrite, nitric oxide (NO) and superoxide, and inducible NO synthase (iNOS) and gp91phox protein expression were compared. Myocardial apoptosis and infarct size were markedly enhanced in adiponectin–/– mice (P<0.01). Formation of NO, superoxide, and their cytotoxic reaction product, peroxynitrite, were all significantly higher in cardiac tissue obtained from adiponectin–/– than from wild-type mice (P<0.01). Moreover, myocardial ischemia/reperfusion–induced iNOS and gp91phox protein expression was further enhanced, but endothelial NOS phosphorylation was reduced in cardiac tissue from adiponectin–/– mice. Administration of the globular domain of adiponectin 10 minutes before reperfusion reduced myocardial ischemia/reperfusion–induced iNOS/gp91phox protein expression, decreased NO/superoxide production, blocked peroxynitrite formation, and reversed proapoptotic and infarct-enlargement effects observed in adiponectin–/– mice.
Conclusion— The present study demonstrates that adiponectin is a natural molecule that protects hearts from ischemia/reperfusion injury by inhibition of iNOS and nicotinamide adenine dinucleotide phosphate-oxidase protein expression and resultant oxidative/nitrative stress.
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