S-Nitrosothiols signal hypoxia-mimetic vascular pathology

Lisa A. Palmer, Allan Doctor, Preeti Chhabra, Mary Lynn Sheram, Victor E. Laubach, Molly Z. Karlinsey, Michael S. Forbes, Timothy Macdonald, Benjamin Gaston

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Abstract

NO transfer reactions between protein and peptide cysteines have been proposed to represent regulated signaling processes. We used the pharmaceutical antioxidant N-acetylcysteine (NAC) as a bait reactant to measure NO transfer reactions in blood and to study the vascular effects of these reactions in vivo. NAC was converted to S-nitroso-N-acetylcysteine (SNOAC), decreasing erythrocytic S-nitrosothiol content, both during wholeblood deoxygenation ex vivo and during a 3-week protocol in which mice received high-dose NAC in vivo. Strikingly, the NAC-treated mice developed pulmonary arterial hypertension (PAH) that mimicked the effects of chronic hypoxia. Moreover, systemic SNOAC administration recapitulated effects of both NAC and hypoxia. eNOS-deficient mice were protected from the effects of NAC but not SNOAC, suggesting that conversion of NAC to SNOAC was necessary for the development of PAH. These data reveal an unanticipated adverse effect of chronic NAC administration and introduce a new animal model of PAH. Moreover, evidence that conversion of NAC to SNOAC during blood deoxygenation is necessary for the development of PAH in this model challenges conventional views of oxygen sensing and of NO signaling.

Original languageEnglish (US)
Pages (from-to)2592-2601
Number of pages10
JournalJournal of Clinical Investigation
Volume117
Issue number9
DOIs
StatePublished - Sep 4 2007
Externally publishedYes

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Palmer, L. A., Doctor, A., Chhabra, P., Sheram, M. L., Laubach, V. E., Karlinsey, M. Z., Forbes, M. S., Macdonald, T., & Gaston, B. (2007). S-Nitrosothiols signal hypoxia-mimetic vascular pathology. Journal of Clinical Investigation, 117(9), 2592-2601. https://doi.org/10.1172/JCI29444