Nitrosopersulfide (SSNO) accounts for sustained NO bioactivity of S-nitrosothiols following reaction with sulfide
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Sulfide salts are known to promote the release of nitric oxide (NO) from S-nitrosothiols and potentiate their vasorelaxant activity, but much of the cross-talk between hydrogen sulfide and NO is believed to occur via functional interactions of cell regulatory elements such as phosphodiesterases. Using RFL-6 cells as an NO reporter system we sought to investigate whether sulfide can also modulate nitrosothiol-mediated soluble guanylyl cyclase (sGC) activation following direct chemical interaction. We find a U-shaped dose response relationship where low sulfide concentrations attenuate sGC stimulation by S-nitrosopenicillamine (SNAP) and cyclic GMP levels are restored at equimolar ratios. Similar results are observed when intracellular sulfide levels are raised by pre-incubation with the sulfide donor, GYY4137. The outcome of direct sulfide/nitrosothiol interactions also critically depends on molar reactant ratios and is accompanied by oxygen consumption. With sulfide in excess, a 'yellow compound' accumulates that is indistinguishable from the product of solid-phase transnitrosation of either hydrosulfide or hydrodisulfide and assigned to be nitrosopersulfide (perthionitrite, SSNO; λ 412nm in aqueous buffers, pH 7.4; 448nm in DMF). Time-resolved chemiluminescence and UV-visible spectroscopy analyses suggest that its generation is preceded by formation of the short-lived NO-donor, thionitrite (SNO). In contrast to the latter, SSNO is rather stable at physiological pH and generates both NO and polysulfides on decomposition, resulting in sustained potentiation of SNAP-induced sGC stimulation. Thus, sulfide reacts with nitrosothiols to form multiple bioactive products; SSNO rather than SNO may account for some of the longer-lived effects of nitrosothiols and contribute to sulfide and NO signaling.
Cortese-Krott , M M , Fernandez , B O , Santos , J L T , Mergia , E , Grman , M , Nagy , P , Kelm , M , Butler , A & Feelisch , M 2014 , ' Nitrosopersulfide (SSNO) accounts for sustained NO bioactivity of S-nitrosothiols following reaction with sulfide ' Redox Biology , vol 2 , no. 1 , pp. 234-244 . DOI: 10.1016/j.redox.2013.12.031
© 2014 The Authors. Published by Elsevier B.V. All rights reserved. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: Susanne-Bunnenberg-Stiftung of the Düsseldorf Heart Center (to MK), the COSTaction BM1005 (European Network on Gasotransmitters), the FP7 Marie Curie International Reintegration program (PIRG08-GA-2010-277006, to PN) and the Faculty of Medicine, University of Southampton (to MF).
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