on April 27, 2006
Published online before print April 27, 2006, doi: 10.1161/01.ATV.0000224324.52466.e6
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Submitted on November 25, 2005
Accepted on April 17, 2006
Cardiomyocyte-Specific Overexpression of NO Synthase-3 Protects Against Myocardial Ischemia-Reperfusion Injury
John W. Elrod ;
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, Massachusetts; 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.
* To whom correspondence should be addressed. 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.
Key words: gene therapy • myocardial infarction • eNOS • cardiomyocyte • endothelial • cardiac function • blood pressure
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