Polysulfides are possible H
            <sub>2</sub>
            S‐derived signaling molecules in rat brain

Kimura, Yoshinobu; Mikami, Yuzuru; Osumi, Kimiko; Tsugane, Mamiko; Oka, Jun-Ichiro; Kimura, Hideo

doi:10.1096/fj.12-226415

Cited by 302 publications

(300 citation statements)

References 39 publications

(62 reference statements)

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“…Effect of sulfide 1, 2 and 5 μM versus 0.5 μM the 'SSNO -mix' was determined using the Dunnett multiple comparison; λλ P < 0.01. must account for the relaxation observed. These may include Sn and SSNO - [12,13,50]. Using EPR spectroscopy we confirmed the release of NO from the reaction mixture, but SSNO -is not known to release HNO.…”

Section: Discussionmentioning

confidence: 65%

The reaction products of sulfide and S-nitrosoglutathione are potent vasorelaxants

et al. 2015

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A B S T R A C TThe chemical interaction of sodium sulfide (Na2S) with the NO-donor S-nitrosoglutathione (GSNO) has been described to generate new reaction products, including polysulfides and nitrosopersulfide (SSNO -) via intermediacy of thionitrous acid (HSNO). The aim of the present work was to investigate the vascular effects of the longer-lived products of the Sulfide/GSNO interaction. Here we show that the products of this reaction relax precontracted isolated rings of rat thoracic aorta and mesenteric artery (but to a lesser degree rat uterus) with a >2-fold potency compared with the starting material, GSNO (50 nM), whereas Na2S and polysulfides have little effect at 1-5 μM. The onset of vasorelaxation of the reaction products was 7-10 times faster in aorta and mesenteric arteries compared with GSNO. Relaxation to GSNO (100-500 nM) was blocked by an inhibitor of soluble guanylyl cyclase, ODQ (0.1 and 10 μM), and by the NO scavenger cPTIO (100 μM), but less affected by prior acidification (pH 2-4), and unaffected by N-acetylcysteine (1 mM) or methemoglobin (20 μM heme). By contrast, relaxation to the Sulfide/GSNO reaction products (100-500 nM based on the starting material) was inhibited to a lesser extent by ODQ, only slightly decreased by cPTIO, more markedly inhibited by methemoglobin and N-acetylcysteine, and abolished by acidification before addition to the organ bath. The reaction mixture was found to generate NO as detected by EPR spectroscopy using N-(dithiocarboxy)-N-methyl-D-glucamine (MGD2)-Fe 2+ as spin trap. In conclusion, the Sufide/GSNO reaction products are faster and more pronounced vasorelaxants than GSNO itself. We conclude that in addition to NO formation from SSNO -, reaction products other than polysulfides may give rise to nitroxyl (HNO) and be involved in the pronounced relaxation induced by the Sulfide/GSNO cross-talk.

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Section: Discussionmentioning

confidence: 65%

The reaction products of sulfide and S-nitrosoglutathione are potent vasorelaxants

et al. 2015

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“…We recently reported that polysulfides induced Ca 2+ influx by activating transient receptor potential (TRP) A1 channels, which have sensitive thiol residues, in rat astrocytes, and a maximal response was induced at 0.5 lM, which is 1/320 of the concentration of H 2 S required to achieve a response of similar magnitude [24]. These findings support the notion that bound sulfur species, such as polysulfides, have direct reactivity independent of H 2 S. Furthermore, a recent report determined that evidence that has been attributed to H 2 S in many previous reports may in fact have been mediated by polysulfides [25].…”

Section: Discussionmentioning

confidence: 99%

Polysulfide exerts a protective effect against cytotoxicity caused by t‐buthylhydroperoxide through Nrf2 signaling in neuroblastoma cells

et al. 2013

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a b s t r a c tPolysulfide is a bound sulfur species derived from endogenous H 2 S. When mouse neuroblastoma, Neuro2A cells were exposed to tert-butyl hydroperoxide after treatment with polysulfide, a significant decline in cell toxicity was observed. Rapid uptake of polysulfides induced translocation of Nrf2 into the nucleus, resulting in acceleration of GSH synthesis and HO-1 expression. We demonstrated that polysulfide reversibly modified Keap1 to form oxidized dimers and induced the translocation of Nrf2. Moreover, polysulfide treatment accelerated Akt phosphorylation, which is a known pathway of Nrf2 phosphorylation. Thus, polysulfide may mediate the activation of Nrf2 signaling, thereby exerting protective effects against oxidative damage in Neuro2A cells.

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“…Accumulation of this product was also observed after reaction of RSNOs with sulfide at pH 7.4 (26,27); moreover, SSNO − -containing mixtures were found to release NO, activate soluble guanylyl cyclase (sGC) (26), and relax vascular tissue (28), although a contribution of other reaction products to these effects cannot be excluded. Meanwhile, other sulfane sulfur molecules, including persulfides (RSSH) and polysulfides (RSS n − and HS n − ), have come to the fore as potential mediators of sulfide's biological effects (29)(30)(31), but little is known about their pathways of formation, prevalence in biological systems, and relationship with NO.…”

Section: Significancementioning

confidence: 99%

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

Cortese‐Krott

Kuhnle

Dyson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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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 reactions between NO and H 2 S/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.sulfide | nitric oxide | nitroxyl | redox | gasotransmitter N itrogen and sulfur are essential for all known forms of life on Earth. Our planet's earliest atmosphere is likely to have contained only traces of O 2 but rather large amounts of hydrogen sulfide (H 2 S) (1). Indeed, sulfide may have supported life long before the emergence of O 2 and NO (2, 3).* This notion is consistent with a number of observations: H 2 S is essential for efficient abiotic amino acid generation as evidenced by the recent reanalysis of samples of Stanley Miller's original spark discharge experiments (4), sulfide is an efficient reductant in protometabolic reactions forming RNA, protein, and lipid precursors (5), and sulfide is both a bacterial and mitochondrial substrate (6), enabling even multicellular lifeforms to exist and reproduce under conditions of permanent anoxia (7). Thus, although eukaryotic cells may have originated from the symbiosis of sulfurreducing and -oxidizing lifeforms within a self-contained sulfur redox metabolome (8), sulfide may have been essential even earlier by providing the basic building blocks of ...

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Polysulfides are possible H ₂ S‐derived signaling molecules in rat brain

Cited by 302 publications

References 39 publications

The reaction products of sulfide and S-nitrosoglutathione are potent vasorelaxants

The reaction products of sulfide and S-nitrosoglutathione are potent vasorelaxants

Polysulfide exerts a protective effect against cytotoxicity caused by t‐buthylhydroperoxide through Nrf2 signaling in neuroblastoma cells

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

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Polysulfides are possible H 2 S‐derived signaling molecules in rat brain

Cited by 302 publications

References 39 publications

The reaction products of sulfide and S-nitrosoglutathione are potent vasorelaxants

The reaction products of sulfide and S-nitrosoglutathione are potent vasorelaxants

Polysulfide exerts a protective effect against cytotoxicity caused by t‐buthylhydroperoxide through Nrf2 signaling in neuroblastoma cells

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

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Polysulfides are possible H ₂ S‐derived signaling molecules in rat brain

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