S-Nitrosothiols signal hypoxia-mimetic vascular pathology
Open Access
- 4 September 2007
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 117 (9), 2592-2601
- https://doi.org/10.1172/jci29444
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.Keywords
This publication has 54 references indexed in Scilit:
- Effect of hypoxic preconditioning on brain genomic response before and following ischemia in the adult mouse: Identification of potential neuroprotective candidates for strokeNeurobiology of Disease, 2006
- NO and transcriptional regulation: from signaling to deathToxicology, 2005
- O2-regulated gene expression: transcriptional control of cardiorespiratory physiology by HIF-1Journal of Applied Physiology, 2004
- FIZZ1/RELMα, a Novel Hypoxia-Induced Mitogenic Factor in Lung With Vasoconstrictive and Angiogenic PropertiesCirculation Research, 2003
- HIF‐1α protein as a target for S‐nitrosationFEBS Letters, 2003
- Characterization of the hypotensive effect of S-nitroso-N-acetylcysteine in normotensive and hypertensive conscious ratsNitric Oxide, 2002
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001
- Independent function of two destruction domains in hypoxia-inducible factor-α chains activated by prolyl hydroxylationThe EMBO Journal, 2001
- Induction of Hypoxia-Inducible-Factor 1 by Nitric Oxide Is Mediated via the PI 3K PathwayBiochemical and Biophysical Research Communications, 2000
- Upregulation of Nitric Oxide Synthase Correlates Temporally With Onset of Pulmonary Vascular Remodeling in the Hypoxic RatHypertension, 1996