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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1517.)
© 2006 American Heart Association, Inc.

Vascular Biology

Cardiomyocyte-Specific Overexpression of NO Synthase-3 Protects Against Myocardial Ischemia-Reperfusion Injury

John W. Elrod; James J.M. Greer; Nathan S. Bryan; Will Langston; Jeffrey F. Szot; Henock Gebregzlabher; Stefan Janssens; Martin Feelisch; David J. Lefer

From the Department of Medicine (J.W.E., D.J.L.), Division of Cardiology, Albert Einstein College of Medicine, Bronx, NY; Department of Molecular and Cellular Physiology (J.J.M.G., W.L., J.F.S.), LSU Health Sciences Center, Shreveport, La; Department of Medicine (N.S.B., M.F.), Boston University Medical Center, Whitaker Cardiovascular Institute, Mass; Department of Medicine (H.G.), LSU Health Sciences Center, Shreveport, La; and Cardiology Division and Center for Transgene Technology and Gene Therapy (S.J.), University of Leuven, Leuven, Belgium.

Correspondence to David J. Lefer, PhD, Albert Einstein College of Medicine, Division of Cardiology, 1300 Morris Park Ave, Bronx, NY 10461. E-mail dlefer{at}aecom.yu.edu

Objective— The protective effect of NO synthase-3 (eNOS)–derived NO in limiting myocardial ischemia-reperfusion (MI-R) injury is well established. We reported previously that systemic genetic overexpression of eNOS attenuates MI-R injury. The purpose of the current study was to investigate tissue-specific genetic overexpression of the human eNOS gene.

Methods and Results— To accomplish this, we used 2 distinct murine models of transgenic overexpression, a cardiomyocyte-specific eNOS overexpresser (CS eNOS-Tg) under the control of the -myosin heavy chain promoter, and a systemic eNOS transgenic mouse (SYS eNOS-Tg) under control of the native eNOS promoter with an upstream endothelial enhancer element. Mice were subjected to 30 or 45 minutes of left coronary artery ischemia and 24 or 72 hours of reperfusion. CS eNOS-Tg mice displayed significantly decreased infarct size beyond that of mice with systemic overexpression. Additionally, CS eNOS-Tg mice exhibited better preservation of cardiac function compared with SYS eNOS-Tg mice after myocardial infarction.

Conclusion— These results provide evidence that site-specific targeting of eNOS gene therapy may be more advantageous in limiting MI-R injury and subsequent cardiac dysfunction.

Cardiomyoctye-specific eNOS overexpression (CS eNOS-Tg) versus systemic overexpression (SYS eNOS-Tg) was evaluated in MI-R injury. CS eNOS-Tg mice displayed decreased infarct size and preservation of cardiac function compared with SYS eNOS-Tg mice. These results provide evidence that site-specific targeting of eNOS gene therapy may be more advantageous in limiting MI-R injury.

Key Words: gene therapy • myocardial infarction • eNOS • cardiomyocyte • endothelial • cardiac function • blood pressure

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