Endothelial nitric oxide synthase (NOS3) knockout decreases NOS2 induction, limiting hyperoxygenation and conferring protection in the postischemic heart

Xue Zhao, Yeong Renn Chen, Guanglong He, Aiwen Zhang, Lawrence J. Druhan, Arthur R. Strauch, Jay L. Zweier

Research output: Contribution to journalArticlepeer-review

Abstract

Although it has been shown that endothelial nitric oxide synthase (eNOS)-derived nitric oxide downregulates mitochondrial oxygen consumption during early reperfusion, its effects on inducible NOS (iNOS) induction and myocardial injury during late reperfusion are unknown. Wild-type (WT) and eNOS-/- mice were subjected to 30 min of coronary ligation followed by reperfusion. Expression of iNOS mRNA and protein levels and peroxynitrite production were lower in postischemic myocardium of eNOS-/- mice than levels in WT mice 48 h postreperfusion. Significantly improved hemodynamics (±dP/dt, left ventricular systolic pressure, mean arterial pressure), increased rate pressure product, and reduced myocardial infarct size (18 ± 2.5% vs. 31 ± 4.6%) were found 48 h after reperfusion in eNOS-/- mice compared with WT mice. Myocardial infarct size was also significantly decreased in WT mice treated with the specific iNOS inhibitor 1400W (20.5 ± 3.4%) compared with WT mice treated with PBS (33.9 ± 5.3%). A marked reperfusion-induced hyperoxygenation state was observed by electron paramagnetic resonance oximetry in postischemic myocardium, but PO 2 values were significantly lower from 1 to 72 h in eNOS -/- than in WT mice. Cytochrome c-oxidase activity and NADH dehydrogenase activity were significantly decreased in postischemic myocardium in WT and eNOS-/- mice compared with baseline control, respectively, and NADH dehydrogenase activity was significantly higher in eNOS-/- than in WT mice. Thus deficiency of eNOS exerted a sustained beneficial effect on postischemic myocardium 48 h after reperfusion with preserved mitochondrial function, which appears to be due to decreased iNOS induction and decreased iNOS-derived peroxynitrite in postischemic myocardium.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume292
Issue number3
DOIs
StatePublished - Mar 2007
Externally publishedYes

Keywords

  • Electron paramagnetic resonance
  • Ischemia-reperfusion
  • Mitochondria
  • Oxygen
  • Peroxynitrite
  • Superoxide

ASJC Scopus subject areas

  • Physiology

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