title: Nitrite protects against morbidity and mortality associated with TNF- or LPS-induced shock in a soluble guanylate cyclase-dependent manner.
abstract: Nitrite (NO(2)(-)), 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) alpha1 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.
authors.affiliation: Department for Molecular Biomedical Research, Flanders Institute for Biotechnology, 9052 Ghent, Belgium. Anje.Cauwels@dmbr.UGent.be
authors.forename: Anje
authors.initials: A
authors.lastname: Cauwels
authors.forename: Emmanuel S
authors.initials: ES
authors.lastname: Buys
authors.forename: Robrecht
authors.initials: R
authors.lastname: Thoonen
authors.forename: Lisa
authors.initials: L
authors.lastname: Geary
authors.forename: Joris
authors.initials: J
authors.lastname: Delanghe
authors.forename: Sruti
authors.initials: S
authors.lastname: Shiva
authors.forename: Peter
authors.initials: P
authors.lastname: Brouckaert
mesh_terms: D000818:Animals; D005260:Female; D006162:Guanylate Cyclase / Q000502:physiology*; D008070:Lipopolysaccharides / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D012769:Shock / Q000188:drug therapy*; D012977:Sodium Nitrite / Q000627:therapeutic use*; D000071756:Soluble Guanylyl Cyclase; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*
chemical_list: D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D012977:Sodium Nitrite