Affiliation:
1. Department for Molecular Biomedical Research, Flanders Institute for Biotechnology, 9052 Ghent, Belgium
2. Department of Biomedical Molecular Biology and Department of Clinical Chemistry, University Hospital, Ghent University, 9000 Ghent, Belgium
3. Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
4. Department of Pharmacology and Chemical Biology and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
Abstract
Nitrite (NO2−), previously viewed as a physiologically inert metabolite and biomarker of the endogenous vasodilator NO, was recently identified as an important biological NO reservoir in vasculature and tissues, where it contributes to hypoxic signaling, vasodilation, and cytoprotection after ischemia–reperfusion injury. Reduction of nitrite to NO may occur enzymatically at low pH and oxygen tension by deoxyhemoglobin, deoxymyoglobin, xanthine oxidase, mitochondrial complexes, or NO synthase (NOS). We show that nitrite treatment, in sharp contrast with the worsening effect of NOS inhibition, significantly attenuates hypothermia, mitochondrial damage, oxidative stress and dysfunction, tissue infarction, and mortality in a mouse shock model induced by a lethal tumor necrosis factor challenge. Mechanistically, nitrite-dependent protection was not associated with inhibition of mitochondrial complex I activity, as previously demonstrated for ischemia–reperfusion, but was largely abolished in mice deficient for the soluble guanylate cyclase (sGC) α1 subunit, one of the principal intracellular NO receptors and signal transducers in the cardiovasculature. Nitrite could also provide protection against toxicity induced by Gram-negative lipopolysaccharide, although higher doses were required. In conclusion, we show that nitrite can protect against toxicity in shock via sGC-dependent signaling, which may include hypoxic vasodilation necessary to maintain microcirculation and organ function, and cardioprotection.
Publisher
Rockefeller University Press
Subject
Immunology,Immunology and Allergy
Cited by
65 articles.
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