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Cited by 153Sulfur Compounds in BiologyNitric Oxide and Endothelin EffectsRedox biology and oxidative stress

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Nitrosopersulfide (SSNO−) accounts for sustained NO bioactivity of S-nitrosothiols following reaction with sulfide

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Cortese-Krott, Miriam M., Fernandez, Bernadette O., Santos, José L.T., Mergia, Evanthia, Grman, Marian, Nagy, Péter, Kelm, Malte, Butler, Anthony, Feelisch, Martin·2014·Redox Biology
DOI 10.1016/j.redox.2013.12.031PMC PMC3909780
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Abstract

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 max 412 nm in aqueous buffers, pH 7.4; 448 nm 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.

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Graphical abstract
Graphical abstract CC BY · PubMed Central
Fig. 1 Sulfide modulates s-nitrosothiol bioactivity in a concentration-dependent manner. (A) Changes in cGMP concentration after treatment of RFL-6 cells with Na2S, SNAP, or their combination (n=5). (B) Effects of SNAP on cells pre-incubated with the sulfide donor GYY4137 (n=4). (C) Effects of sGC and PDE inhibition on Na2S and GYY4137 induced activation of sGC (n=4). (D) Effects of cPTIO on sulfide and SNAP induced sGC activation (n=3) ⁎p<0.05; ⁎⁎p<0.01 vs. CTRL, # p<0.05, T-test.
Fig. 1 Sulfide modulates s-nitrosothiol bioactivity in a concentration-dependent manner. (A) Changes in cGMP concentration after treatment of RFL-6 cells with Na2S, SNAP, or their combination (n=5). (B) Effects of SNAP on cells pre-incubated with the sulfide donor GYY4137 (n=4). (C) Effects of sGC and PDE inhibition on Na2S and GYY4137 induced activation of sGC (n=4). (D) Effects of cPTIO on sulfide and SNAP induced sGC activation (n=3) ⁎p<0.05; ⁎⁎p<0.01 vs. CTRL, # p<0.05, T-test.CC BY · PubMed Central
Fig. 2 The reaction between sulfide and nitrosothiols leads to formation of NO-releasing species. (A,B) UV–visible spectroscopic analyses of the reaction between SNAP and hydrosulfide at pH 7.4. Varying SNAP/Na2S concentration ratios lead to formation of different products as assessed after 1 min (A) and 10 min of incubation (B); with excess sulfide accumulation of a ‘yellow compound’ (λmax 412 nm) was observed. (C,D) Profiles of NO release from SNAP/Na2S mixtures of different concentration ratios after 1 min (C) or 10 min of incubation (D). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Fig. 2 The reaction between sulfide and nitrosothiols leads to formation of NO-releasing species. (A,B) UV–visible spectroscopic analyses of the reaction between SNAP and hydrosulfide at pH 7.4. Varying SNAP/Na2S concentration ratios lead to formation of different products as assessed after 1 min (A) and 10 min of incubation (B); with excess sulfide accumulation of a ‘yellow compound’ (λmax 412 nm) was observed. (C,D) Profiles of NO release from SNAP/Na2S mixtures of different concentration ratios after 1 min (C) or 10 min of incubation (D). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)CC BY · PubMed Central
Fig. 3 Oxygen consumption by the reaction of SNAP with sulfide. Changes in dissolved oxygen (O2) concentration in air-saturated phosphate buffer pH 7.4 by 1 mM SNAP (green tracing) or 2 mM Na2S alone (yellow), as compared to mixtures of 1 mM SNAP and different concentration of sulfide (1, 2, 10 mM, final concentrations). Representative tracings of 3–4 separate runs at each condition yielding qualitatively identical results. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Fig. 3 Oxygen consumption by the reaction of SNAP with sulfide. Changes in dissolved oxygen (O2) concentration in air-saturated phosphate buffer pH 7.4 by 1 mM SNAP (green tracing) or 2 mM Na2S alone (yellow), as compared to mixtures of 1 mM SNAP and different concentration of sulfide (1, 2, 10 mM, final concentrations). Representative tracings of 3–4 separate runs at each condition yielding qualitatively identical results. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)CC BY · PubMed Central
Fig. 4 Formation of SNO− and SSNO− during the reaction of SNAP or isopentyl nitrite (IPN) with hydrosulfide (HS−) under aqueous and non-aqueous conditions. (A,B) Reaction of Na2S and SNAP in phosphate buffer (PB) at pH 7.4. Green line, starting spectrum of SNAP. Attributions: λmax 320 nm=SNO−; λmax 412 nm=SSNO− (C) Reaction of Na2S and SNAP in DMSO. Spectra taken in the first 60 s after the beginning of the reaction are shown. Attributions λmax 448 nm=SSNO− (D) Reaction of isopentylnitrite (IPN) with Na2S in DMSO. Red line, starting spectrum of IPN. Attributions: λmax 325 nm=ONS−; λmax 448 nm=SSNO−. Time interval for spectra: 0–60 s. Cycle time 0.1 s. Insets in (A–D) are depicting the time course of absorbance changes at 412 nm (A,B) or 448 nm (C,D).
Fig. 4 Formation of SNO− and SSNO− during the reaction of SNAP or isopentyl nitrite (IPN) with hydrosulfide (HS−) under aqueous and non-aqueous conditions. (A,B) Reaction of Na2S and SNAP in phosphate buffer (PB) at pH 7.4. Green line, starting spectrum of SNAP. Attributions: λmax 320 nm=SNO−; λmax 412 nm=SSNO− (C) Reaction of Na2S and SNAP in DMSO. Spectra taken in the first 60 s after the beginning of the reaction are shown. Attributions λmax 448 nm=SSNO− (D) Reaction of isopentylnitrite (IPN) with Na2S in DMSO. Red line, starting spectrum of IPN. Attributions: λmax 325 nm=ONS−; λmax 448 nm=SSNO−. Time interval for spectra: 0–60 s. Cycle time 0.1 s. Insets in (A–D) are depicting the time course of absorbance changes at 412 nm (A,B) or 448 nm (C,D).CC BY · PubMed Central
Fig. 5 Formation of SSNO− from the reaction between sulfide and immobilized S-nitroso moieties. (A) S-nitrosation by acidified nitrite of resin-bound sulfhydryl (–SH) groups (Ekathiol®) to form an immobilized nitrosothiol. (B,C) A solution of either Na2S (B) or Na2S2 (C) is passed over the column and reacts with immobilized S-nitrosothiols to form SSNO− (λmax 412 nm; high sulfide concentration) and polysulfides (<280 nm; lower sulfide concentrations). Depicted results are representative of 4 independent experiments with different batches of nitrosated thiol-containing resin and various absolute amounts of sulfide (0.015–5 µmoles on column).
Fig. 5 Formation of SSNO− from the reaction between sulfide and immobilized S-nitroso moieties. (A) S-nitrosation by acidified nitrite of resin-bound sulfhydryl (–SH) groups (Ekathiol®) to form an immobilized nitrosothiol. (B,C) A solution of either Na2S (B) or Na2S2 (C) is passed over the column and reacts with immobilized S-nitrosothiols to form SSNO− (λmax 412 nm; high sulfide concentration) and polysulfides (<280 nm; lower sulfide concentrations). Depicted results are representative of 4 independent experiments with different batches of nitrosated thiol-containing resin and various absolute amounts of sulfide (0.015–5 µmoles on column).CC BY · PubMed Central
Fig. 6 Decomposition of SSNO− releases NO and activates of sGC. (A) UV–visible spectra (main panel) and chemiluminescent profile of NO release (inset) of a SNAP/Na2S mixtures (1:10) at pH 7.4 following 1 min (gray) or 10 min (orange) of incubation at RT in 1 M TRIS buffer, pH 7.4. (B) Original chemiluminescence tracing of NO release over time of a SNAP/Na2S mixture (1:10) incubated for the indicated time points. Inset: changes in total NO release (area under the curve) with increasing time of preincubation. (C) Dose-dependent sGC activation by the SNAP/Na2S mixture (1:10) incubated for 10 min (SSNO− mix) compared to the same volumes of a control mix prepared with SNAP only (SNAP mix). (D) NO and sGC dependent cGMP increase in RFL-6 cells after incubation with 20 µl of the SSNO− mix compared to the effects of SNAP and sulfide (Na2S) alone. “+Zn2+” denotes removal of excess sulfide by zinc precipitation; indicated volumes were added directly to the cell culture medium to reach a total volume of 1 ml. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Fig. 6 Decomposition of SSNO− releases NO and activates of sGC. (A) UV–visible spectra (main panel) and chemiluminescent profile of NO release (inset) of a SNAP/Na2S mixtures (1:10) at pH 7.4 following 1 min (gray) or 10 min (orange) of incubation at RT in 1 M TRIS buffer, pH 7.4. (B) Original chemiluminescence tracing of NO release over time of a SNAP/Na2S mixture (1:10) incubated for the indicated time points. Inset: changes in total NO release (area under the curve) with increasing time of preincubation. (C) Dose-dependent sGC activation by the SNAP/Na2S mixture (1:10) incubated for 10 min (SSNO− mix) compared to the same volumes of a control mix prepared with SNAP only (SNAP mix). (D) NO and sGC dependent cGMP increase in RFL-6 cells after incubation with 20 µl of the SSNO− mix compared to the effects of SNAP and sulfide (Na2S) alone. “+Zn2+” denotes removal of excess sulfide by zinc precipitation; indicated volumes were added directly to the cell culture medium to reach a total volume of 1 ml. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)CC BY · PubMed Central

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Research works printed but not linked: 1

  1. Seel, 1985, PNP-Perthionitrit und PNP-Monothionitrit. Zeitschrift für Naturforschung, Teil b, Anorg. Chemie, Org. Chem., 40, 1607

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Authors
Cortese-Krott, M. M., Fernandez, B. O., Santos, J. L. T., Mergia, E., Grman, M., Nagy, P., Kelm, M., Butler, A., & Feelisch, M.
Affiliations
  • Heinrich Heine University Düsseldorf (DE)
  • Southampton General Hospital (GB)
  • Ruhr University Bochum (DE)
  • Slovak Academy of Sciences (SK)
  • National Institute of Oncology (HU)
  • University of St Andrews (GB)
Corresponding author
Feelisch, Martin
ORCID
Venue
Redox Biology
Publisher
Elsevier BV
Published
2014
Volume
2
Pages
234-244
ISSN
2213-2317 (ISSN-L)
DOI
10.1016/j.redox.2013.12.031
PMC
PMC3909780
OpenAlex
W2037151440
Cited by
153
References
64
Citations by year
2026: 6 · 2025: 11 · 2024: 6 · 2023: 7 · 2022: 7 · 2021: 5 · 2020: 17 · 2019: 11 · 2018: 12 · 2017: 22 · 2016: 20 · 2015: 14 · 2014: 14
FWCI
10.37
Type
journal article
Language
en
Open access
Licence
Locations
  • Redox Biology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ePrints Soton (University of Southampton) (acceptedVersion)
  • University of Debrecen Electronic Archive (University of Debrecen) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • St Andrews Research Repository (St Andrews Research Repository) (submittedVersion, cc-by)
Funders
  • European Network on Gasotransmitters
  • FP7 Marie Curie International Reintegration program (PIRG08-GA-2010-277006, to PN)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
  • Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords
S-nitrosothiols, sulfide, nitric oxide, hydrogen sulfide signaling, transnitrosation, thionitrites, GYY4137, cyclic GMP, polysulfides, oxygen consumption
MeSH terms
Soluble Guanylyl Cyclase, Animals, Cell Line, Cyclic GMP, Guanylate Cyclase, Morpholines, Nitric Oxide, Nitroso Compounds, Organothiophosphorus Compounds, Oxygen Consumption, Sulfides, Receptors, Cytoplasmic and Nuclear, Nitric Oxide Donors, S-Nitrosothiols, Rats

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