Cardioprotection afforded by inducible nitric oxide synthase gene therapy is mediated by cyclooxygenase-2 via a nuclear factor-κB-dependent pathway

Qianhong Li, Yiru Guo, Wei Tan, Qinghui Ou, Wen Jian Wu, Diana Sturza, Buddhadeb Dawn, Greg Hunt, Chuanjue Cui, Roberto Bolli

Research output: Contribution to journalArticlepeer-review

Abstract

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)-κB-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 IκBα (IκBα), the upregulation of phosphorylated IκBα, activation of NF-κB, 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-κB is a critical link between iNOS and COX-2. Thus, iNOS imparts its protective effects, at least in part, by recruiting NF-κB, leading to COX-2 upregulation. However, COX-2 does not play an important cardioprotective role under basal conditions (when iNOS is not upregulated).

Original languageEnglish (US)
Pages (from-to)1577-1584
Number of pages8
JournalCirculation
Volume116
Issue number14
DOIs
StatePublished - Oct 2007

Keywords

  • Cyclooxygenase 2
  • Gene therapy
  • Myocardial infarction
  • NF-kappa B
  • Nitric oxide synthase

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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