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1 Institute of Molecular Cardiology, Louisville, KY, USA
2 Department of Neurological Surgery, University of Louisville, Louisville, KY, USA
* To whom correspondence should be addressed. E-mail: rbolli{at}louisville.edu.
Previous studies have shown that gene therapy with inducible nitric oxide synthase (iNOS) protects against myocardial infarction at 3 days after gene transfer. However, the long-term effects of iNOS gene therapy on myocardial ischemic injury and cardiac function are unknown. To address this issue, we used an Ad5 vector (Av3) with deletions of the E1, E2a, and E3 regions, which enables long-lasting recombinant gene expression for at least 2 months due to lack of inflammation. Mice received intramyocardial injections in the left ventricular (LV) anterior wall of Av3/LacZ (LacZ group) or Av3/iNOS (iNOS group); 1 or 2 months later, they were subjected to myocardial infarction (30-min coronary occlusion followed by 4 h of reperfusion). Cardiac iNOS gene expression was confirmed by immunoblotting and activity assays at 1 and 2 months after gene transfer. In the iNOS group, infarct size (% of risk region) was significantly reduced (P<0.05) both at 1 month (24.2+/-3.4%, n=6, vs. 48.0+/-3.6%, n=8, in LacZ group) and at 2 months (23.4+/-3.1%, n=8, vs. 36.6+/-2.4%, n=7). The infarct-sparing effects of iNOS gene therapy were as powerful as those observed 24 h after ischemic preconditioning (23.1+/-3.4%, n=10). iNOS gene transfer had no effect on LV function or dimensions up to 8 weeks later (echocardiograghy). These data demonstrate that iNOS gene therapy mediated by the Av3 vector affords long-term (2 months) cardioprotection without inflammation or adverse functional consequences, a finding that provides a rationale for further preclinical testing of this therapy.
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