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S-Nitrosothiols signal hypoxia-mimetic vascular pathology
Lisa A. Palmer, … , Timothy Macdonald, Benjamin Gaston
Lisa A. Palmer, … , Timothy Macdonald, Benjamin Gaston
Published September 4, 2007
Citation Information: J Clin Invest. 2007;117(9):2592-2601. https://doi.org/10.1172/JCI29444.
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Research Article

S-Nitrosothiols signal hypoxia-mimetic vascular pathology

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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 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

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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Figure 1

Systemic NAC and SNOAC cause hypoxia-mimetic PAH in mice.

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Systemic NAC and SNOAC cause hypoxia-mimetic PAH in mice.
C57BL/6/129SvE...
C57BL/6/129SvEv, C57BL/6, and eNOS–/– male mice were maintained in normoxia (N, red; 21% O2) or hypoxia (H, black; 10% O2); or were treated with NAC (blue) or SNOAC (green) in their drinking water for 3 weeks. (A) Relative RV weight was determined as the ratio of the weight of the RV to the LV+S weight. (B) RV systolic pressures were measured in the closed chest using a Millar 1.4 F catheter/transducer. (C) Representative RV pressure (RVP) tracings (each = 1 s). (D) Lung section images from C57BL/6/129SvEv mice immunostained for von Willebrand factor and α-SMA to illustrate changes in muscularization after 3 weeks of exposure to normoxia, hypoxia, NAC, or SNOAC. Scale bar: 100 μm (applies to all panels). (E) Changes in muscularization in C57BL/6/129SvEv mice in the small (<80-μm) vessels from histological sections (as in D) counted by an observer blinded to the protocol. FM, fully muscular; PM, partly muscular, NM, nonmuscular. Significant increases in muscularization in each treatment group were seen in comparison to normoxic controls. Data are mean ± SEM. ζP < 0.02, *P < 0.001, †P < 0.003, by 1-way ANOVA followed by pairwise comparison, all compared with normoxic control.
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