Key bioactive reaction products of the NO/H 2 S interaction are S/N-hybrid species, polysulfides, and nitroxyl

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-08, Vol.112 (34)
• Main Authors: Cortese-Krott, Miriam M., Kuhnle, Gunter G. C., Dyson, Alex, Fernandez, Bernadette O., Grman, Marian, DuMond, Jenna F., Barrow, Mark P., McLeod, George, Nakagawa, Hidehiko, Ondrias, Karol, Nagy, Péter, King, S. Bruce, Saavedra, Joseph E., Keefer, Larry K., Singer, Mervyn, Kelm, Malte, Butler, Anthony R., Feelisch, Martin
• Format: Article
• Language: English
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1509277112

Reactions of sulfur-centered nucleophiles with nitrogenous species have been studied independently for more than a century for synthetic/industrial purposes; to understand geochemical, atmospheric, and biological processes; and to explain the origins of life. Various products and reaction mechanisms were proposed. We here identify a singular process comprising a network of cascading chemical reactions that form three main bioactive products at physiological pH: nitrosopersulfide, polysulfides, and dinitrososulfite. These anionic products scavenge, transport, and release NO/HNO or sulfide/sulfane sulfur, each displaying distinct chemistries and bioactivities. Our observations provide a chemical foundation for the cross-talk between the NO and H 2 S signaling pathways in biology and suggest that the biological actions of these entities can be neither considered nor studied in isolation. Experimental evidence suggests that nitric oxide (NO) and hydrogen sulfide (H 2 S) 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 H 2 S/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 N 2 O 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 react