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

Key bioactive reaction products of the NO/H2S interaction are S/N-hybrid species, polysulfides, and nitroxyl
Key bioactive reaction products of the NO/H2S interaction are S/N-hybrid species, polysulfides, and nitroxyl
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
0027-8424
1-10
Cortese-Krott, M.
a7240a00-bb40-407c-82d8-f268c6fd12bb
Kuhnle, G.
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Fernandez, B.O.
9890aabc-1fe6-4530-a51e-31182e537131
Grman, M.
df632308-93b8-45d3-b802-5489a0c476cb
DuMond, J.
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Barrow, M.
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McLeod, G.
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Nakagawa, H.
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Ondrias, K.
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Nagy, P.
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King, B.
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Saavedra, J.
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Keefer, L.
121a161f-a8fd-4e00-a717-67bdda17c720
Singer, M.
c73d3e5b-b634-4d6f-98f2-1d230a51797f
Kelm, M.
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Butler, A.
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Feelisch, M.
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Cortese-Krott, M.
a7240a00-bb40-407c-82d8-f268c6fd12bb
Kuhnle, G.
f10f3eeb-b130-4fcf-8662-bf5570414930
Fernandez, B.O.
9890aabc-1fe6-4530-a51e-31182e537131
Grman, M.
df632308-93b8-45d3-b802-5489a0c476cb
DuMond, J.
1a9efa96-5da1-4488-8f02-7b3a00244ef0
Barrow, M.
6438da14-6a0d-4e6b-8803-c6cdef3e4928
McLeod, G.
517ea1fd-bf25-42ca-b4d5-fbad500c7478
Nakagawa, H.
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Ondrias, K.
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Nagy, P.
0dac0a38-2479-4299-950c-09c79b3d93e1
King, B.
4bbe8553-73c9-41ce-bf3b-e8aa075802a4
Saavedra, J.
69695bbd-0ba5-4c22-8d88-2d88e76d96e9
Keefer, L.
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Singer, M.
c73d3e5b-b634-4d6f-98f2-1d230a51797f
Kelm, M.
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Butler, A.
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Feelisch, M.
8c1b9965-8614-4e85-b2c6-458a2e17eafd

Cortese-Krott, M., Kuhnle, G., Fernandez, B.O., Grman, M., DuMond, J., Barrow, M., McLeod, G., Nakagawa, H., Ondrias, K., Nagy, P., King, B., Saavedra, J., Keefer, L., Singer, M., Kelm, M., Butler, A. and Feelisch, M. (2015) Key bioactive reaction products of the NO/H2S interaction are S/N-hybrid species, polysulfides, and nitroxyl. Proceedings of the National Academy of Sciences, 1-10. (doi:10.1073/pnas.1509277112). (PMID:26224837)

Record type: Article

Abstract

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.

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2015_Key Bioactive Reaction products of NO and H2S_Cortese-Krott.pdf - Accepted Manuscript
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Accepted/In Press date: 2 July 2015
Published date: 29 July 2015
Keywords: gasotransmitter, nitric oxide, nitroxyl, redox, sulfide
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 379847
URI: https://eprints.soton.ac.uk/id/eprint/379847
ISSN: 0027-8424
PURE UUID: 28f72557-2df1-4fec-a3f6-4c253ae71caf
ORCID for B.O. Fernandez: ORCID iD orcid.org/0000-0001-6337-0381
ORCID for M. Feelisch: ORCID iD orcid.org/0000-0003-2320-1158

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Date deposited: 06 Aug 2015 16:00
Last modified: 25 Apr 2019 00:31

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Contributors

Author: M. Cortese-Krott
Author: G. Kuhnle
Author: B.O. Fernandez ORCID iD
Author: M. Grman
Author: J. DuMond
Author: M. Barrow
Author: G. McLeod
Author: H. Nakagawa
Author: K. Ondrias
Author: P. Nagy
Author: B. King
Author: J. Saavedra
Author: L. Keefer
Author: M. Singer
Author: M. Kelm
Author: A. Butler
Author: M. Feelisch ORCID iD

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