Nitrite Protects against Morbidity and Mortality Associated with TNF- or LPS-Induced Shock in a Soluble Guanylate Cyclase–Dependent Manner

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Nitrite Protects against Morbidity and Mortality Associated with TNF- or LPS-Induced Shock in a Soluble Guanylate Cyclase–Dependent Manner

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Title: Nitrite Protects against Morbidity and Mortality Associated with TNF- or LPS-Induced Shock in a Soluble Guanylate Cyclase–Dependent Manner
Author: Cauwels, Anje; Thoonen, Robrecht; Geary, Lisa; Delanghe, Joris; Shiva, Sruti; Brouckaert, Peter; Buys, Emmanuel

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Citation: Cauwels, Anje, Emmanuel S. Buys, Robrecht Thoonen, Lisa Geary, Joris Delanghe, Sruti Shiva, and Peter Brouckaert. 2009. Nitrite protects against morbidity and mortality associated with TNF- or LPS-induced shock in a soluble guanylate cyclase–dependent manner. The Journal of Experimental Medicine 206(13): 2915-2924.
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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) \(\alpha\) 1 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.
Published Version: doi://10.1084/jem.20091236
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806477/pdf/
www.jem.org/cgi/doi/10.1084/jem.20091236
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:10178126
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