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on September 4, 2007

Circulation. 2007
Published online before print September 4, 2007, doi: 10.1161/CIRCULATIONAHA.107.689810
A more recent version of this article appeared on October 2, 2007
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Submitted on January 12, 2007
Accepted on July 31, 2007

Cardioprotection Afforded by Inducible Nitric Oxide Synthase Gene Therapy Is Mediated by Cyclooxygenase-2 via a Nuclear Factor-{kappa}B–Dependent Pathway

Qianhong Li MD, PhD, Yiru Guo MD, Wei Tan MD, Qinghui Ou MD, Wen-Jian Wu MSc, Diana Sturza MD, Buddhadeb Dawn MD, Greg Hunt BS, Chuanjue Cui MD, and Roberto Bolli MD*

From the Institute of Molecular Cardiology, University of Louisville, Louisville, Ky.

* To whom correspondence should be addressed. E-mail: rbolli{at}louisville.edu.

Background—Gene therapy with inducible nitric oxide synthase (iNOS) markedly reduces myocardial infarct size; this effect is associated with cyclooxygenase-2 (COX-2) upregulation and is ablated by COX-2 inhibitors. However, pharmacological inhibitors are limited by relative lack of specificity; furthermore, the mechanism whereby iNOS gene therapy upregulates COX-2 remains unknown. Accordingly, we used genetically engineered mice to test the hypothesis that the cardioprotection afforded by iNOS gene transfer is mediated by COX-2 upregulation via a nuclear factor (NF)-{kappa}B–dependent pathway.

Methods and Results—Mice received an intramyocardial injection of Av3/LacZ (LacZ group) or Av3/iNOS (iNOS group); 3 days later, myocardial infarction was produced by a 30-minute coronary occlusion followed by 4 hours of reperfusion. Among Av3/LacZ-treated mice, infarct size was similar in COX-2-/- and wild-type groups. iNOS gene transfer (confirmed by iNOS immunoblotting and activity assays) markedly reduced infarct size in wild-type mice but failed to do so in COX-2-/- mice. In transgenic mice with cardiac-specific expression of a dominant-negative mutant of I{kappa}B{alpha} (I{kappa}B{alpha}S32A,S36A), the upregulation of phosphorylated I{kappa}B{alpha}, activation of NF-{kappa}B, and cardiac COX-2 protein expression 3 days after iNOS gene therapy were abrogated, which was associated with the abolishment of the cardioprotective effects afforded by iNOS gene therapy.

Conclusions—These data provide strong genetic evidence that COX-2 is an obligatory downstream effector of iNOS-dependent cardioprotection and that NF-{kappa}B is a critical link between iNOS and COX-2. Thus, iNOS imparts its protective effects, at least in part, by recruiting NF-{kappa}B, leading to COX-2 upregulation. However, COX-2 does not play an important cardioprotective role under basal conditions (when iNOS is not upregulated).


Key words: nitric oxide synthase • gene therapy • myocardial infarction • NF-kappa B • cyclooxygenase 2




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