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Am J Physiol Heart Circ Physiol 290: H584-H589, 2006. First published September 19, 2005; doi:10.1152/ajpheart.00855.2005
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Gene therapy with iNOS provides long-term protection against myocardial infarction without adverse functional consequences

Qianhong Li,1 Yiru Guo,1 Wei Tan,1 Adam B. Stein,1 Buddhadeb Dawn,1 Wen-Jian Wu,1 Xiaoping Zhu,1 Xiaoqin Lu,1 Xiaoming Xu,2 Tariq Siddiqui,1 Sumit Tiwari,1 and Roberto Bolli1

1Institute of Molecular Cardiology and the 2Department of Neurological Surgery, University of Louisville, Louisville, Kentucky

Submitted 11 August 2005 ; accepted in final form 7 September 2005

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 a recombinant adenovirus 5 (Ad5) vector (Av3) with deletions of the E1, E2a, and E3 regions, which enables long-lasting recombinant gene expression for at least 2 mo 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 mo 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 mo after gene transfer. In the iNOS group, infarct size (percentage of risk region) was significantly reduced (P < 0.05) both at 1 mo (24.2 ± 3.4%, n = 6, vs. 48.0 ± 3.6%, n = 8, in the LacZ group) and at 2 mo (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 wk later (echocardiography). These data demonstrate that iNOS gene therapy mediated by the Av3 vector affords long-term (2 mo) cardioprotection without inflammation or adverse functional consequences, a finding that provides a rationale for further preclinical testing of this therapy.

nitric oxide synthase; cardiac function; mouse


Address for reprint requests and other correspondence: R. Bolli, Div. of Cardiology, Univ. of Louisville, Louisville, KY 40292 (e-mail: rbolli{at}louisville.edu)




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