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Proc Natl Acad Sci U S A. 2015 Aug 25;112(34):E4651-60. doi: 10.1073/pnas.1509277112. Epub 2015 Jul 29.

Key bioactive reaction products of the NO/H2S interaction are S/N-hybrid species, polysulfides, and nitroxyl.

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Cardiovascular Research Laboratory, Department of Cardiology, Pneumology and Angiology, Medical Faculty, Heinrich Heine University of Düsseldorf, 40225 Dusseldorf, Germany;
Department of Nutrition, University of Reading, Whiteknights, Reading RG6 6AP, United Kingdom;
Bloomsbury Institute of Intensive Care Medicine, University College London, London WC1E 6BT, United Kingdom;
Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital and Institute for Life Sciences, Southampton SO16 6YD, United Kingdom;
Center for Molecular Medicine, Slovak Academy of Sciences, 83101 Bratislava, Slovak Republic;
Department of Chemistry, Wake Forest University, Winston-Salem, NC 27109;
Department of Chemistry, Warwick University, Coventry CV4 7AL, United Kingdom;
Bruker UK Ltd., Coventry CV4 9GH, United Kingdom;
Department of Organic and Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya-shi, Aichi 467-8603, Japan;
Department of Molecular Immunology and Toxicology, National Institute of Oncology, 1122 Budapest, Hungary;
Leidos Biomedical Research, Inc., National Cancer Institute-Frederick, Frederick, MD 21702;
National Cancer Institute-Frederick, Frederick, MD 21702;
Medical School, University of St. Andrews, St. Andrews, Fife KY16 9AJ, Scotland.
Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital and Institute for Life Sciences, Southampton SO16 6YD, United Kingdom;


Experimental evidence suggests that nitric oxide (NO) and hydrogen sulfide (H2S) signaling pathways are intimately intertwined, with mutual attenuation or potentiation of biological responses in the cardiovascular system and elsewhere. The chemical basis of this interaction is elusive. Moreover, polysulfides recently emerged as potential mediators of H2S/sulfide signaling, but their biosynthesis and relationship to NO remain enigmatic. We sought to characterize the nature, chemical biology, and bioactivity of key reaction products formed in the NO/sulfide system. At physiological pH, we find that NO and sulfide form a network of cascading chemical reactions that generate radical intermediates as well as anionic and uncharged solutes, with accumulation of three major products: nitrosopersulfide (SSNO(-)), polysulfides, and dinitrososulfite [N-nitrosohydroxylamine-N-sulfonate (SULFI/NO)], each with a distinct chemical biology and in vitro and in vivo bioactivity. SSNO(-) is resistant to thiols and cyanolysis, efficiently donates both sulfane sulfur and NO, and potently lowers blood pressure. Polysulfides are both intermediates and products of SSNO(-) synthesis/decomposition, and they also decrease blood pressure and enhance arterial compliance. SULFI/NO is a weak combined NO/nitroxyl donor that releases mainly N2O on decomposition; although it affects blood pressure only mildly, it markedly increases cardiac contractility, and formation of its precursor sulfite likely contributes to NO scavenging. Our results unveil an unexpectedly rich network of coupled chemical reactions between NO and H2S/sulfide, suggesting that the bioactivity of either transmitter is governed by concomitant formation of polysulfides and anionic S/N-hybrid species. This conceptual framework would seem to offer ample opportunities for the modulation of fundamental biological processes governed by redox switching and sulfur trafficking.


gasotransmitter; nitric oxide; nitroxyl; redox; sulfide

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