Ischemic preconditioning increases iNOS transcript levels in conscious rabbits via a nitric oxide-dependent mechanism

Keith K. Jones, Michael P. Flaherty, Xian Liang Tang, Hitoshi Takano, Yumin Qiu, Supratim Banerjee, Traci Smith, Roberto Bolli

Research output: Contribution to journalArticle

Abstract

Recent studies implicate iNOS as the mediator of the late phase of ischemic preconditioning (PC). However, it is unknown whether induction of iNOS activity is mediated by transcriptional, post-transcriptional, translational, or post-translational mechanisms. To address this issue, we isolated and sequenced a partial iNOS cDNA expressed in preconditioned rabbit myocardium. Using a rabbit-specific probe generated from this sequence, we measured the steady state levels of the iNOS transcript after ischemic PC [six cycles of 4-min occlusion/4-min reperfusion (O/R)]. Three hours after ischemic PC, the iNOS mRNA levels in the ischemic/reperfused region were increased approximately three-fold relative to samples From the non-ischemic region and from control rabbits. This increase in mRNA levels was completely abolished by pretreatment with the NOS inhibitor N(ω)-nitro-L-arginine. Conversely, administration of the NO donor nitroglycerin induced an increase in iNOS mRNA levels similar to that induced by ischemic PC. The conclude that in the conscious rabbit, ischemic PC induces an increase in in;OS mRNA levels, and that this induction is triggered by increased generation of NO during the PC stimulus. These results provide direct evidence that upregulation of iNOS is a natural response of the heart to a brief ischemic stress and that NO itself, in the absence of ischemia, upregulates myocardial iNOS transcript levels, a finding that may have implications for nitrate therapy. This previously unrecognized NO-dependent upregulation of iNOS mRNA is likely to play an important role in the development of late PC as well as in many other pathophisiological conditions in which NO is implicated.

Original languageEnglish (US)
Pages (from-to)1469-1481
Number of pages13
JournalJournal of Molecular and Cellular Cardiology
Volume31
Issue number8
DOIs
StatePublished - Aug 1999

Keywords

  • Ischemia
  • Rabbit
  • iNOS

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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