Gene transfer of inducible nitric oxide synthase affords cardioprotection by upregulating heme oxygenase-1 via a nuclear factor-κb-dependent pathway

Academic Article

Abstract

  • BACKGROUND-: Although inducible nitric oxide synthase (iNOS) is known to impart powerful protection against myocardial infarction, the mechanism for this salubrious action remains unclear. METHODS AND RESULTS-: Adenovirus-mediated iNOS gene transfer in mice resulted 48 to 72 hours later in increased expression not only of iNOS protein but also of heme oxygenase (HO)-1 mRNA and protein; HO-2 protein expression did not change. iNOS gene transfer markedly reduced infarct size in wild-type mice, but this effect was completely abrogated in HO-1 mice. At 48 hours after iNOS gene transfer, nuclear factor-κB was markedly activated. In transgenic mice with cardiomyocyte-restricted expression of a dominant negative mutant of IκBα (IκBα), both basal HO-1 levels and upregulation of HO-1 by iNOS gene transfer were suppressed. Chromatin immunoprecipitation analysis of mouse hearts provided direct evidence that nuclear factor-κB subunits p50 and p65 were recruited to the HO-1 gene promoter (-468 to-459 bp) 48 hours after iNOS gene transfer. CONCLUSIONS-: This study demonstrates for the first time the existence of a close functional coupling between cardiac iNOS and cardiac HO-1: iNOS upregulates HO-1 by augmenting nuclear factor-κB binding to the region of the HO-1 gene promoter from-468 to-459 bp, and HO-1 then mediates the cardioprotective effects of iNOS. These results also reveal an important role of nuclear factor-κB in both basal and iNOS-induced expression of cardiac HO-1. Collectively, the present findings significantly expand our understanding of the regulation of cardiac HO-1 and of the mechanism whereby iNOS exerts its cardioprotective actions. © 2009 American Heart Association, Inc.
  • Authors

    Published In

  • Circulation  Journal
  • Digital Object Identifier (doi)

    Author List

  • Li Q; Guo Y; Ou Q; Cui C; Wu WJ; Tan W; Zhu X; Lanceta LB; Sanganalmath SK; Dawn B
  • Start Page

  • 1222
  • End Page

  • 1230
  • Volume

  • 120
  • Issue

  • 13