title: S-nitrosothiols signal hypoxia-mimetic vascular pathology.
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 whole-blood 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.
authors.affiliation: Department of Pediatrics, University of Virginia School of Medicine, Virginia 22908, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Palmer
authors.forename: Allan
authors.initials: A
authors.lastname: Doctor
authors.forename: Preeti
authors.initials: P
authors.lastname: Chhabra
authors.forename: Mary Lynn
authors.initials: ML
authors.lastname: Sheram
authors.forename: Victor E
authors.initials: VE
authors.lastname: Laubach
authors.forename: Molly Z
authors.initials: MZ
authors.lastname: Karlinsey
authors.forename: Michael S
authors.initials: MS
authors.lastname: Forbes
authors.forename: Timothy
authors.initials: T
authors.lastname: Macdonald
authors.forename: Benjamin
authors.initials: B
authors.lastname: Gaston
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology; D006973:Hypertension / Q000503:physiopathology; D000860:Hypoxia / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D009574:Nitro Compounds / Q000494:pharmacology; D009603:Nitroso Compounds / Q000737:chemistry / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism; D011651:Pulmonary Artery / Q000473:pathology* / Q000503:physiopathology; D026403:S-Nitrosothiols / Q000378:metabolism*; D015398:Signal Transduction