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Nitrosopersulfide (SSNO(-)) targets the Keap-1/Nrf2 redox system.

Nitrosopersulfide (SSNO(-)) targets the Keap-1/Nrf2 redox system.
Nitrosopersulfide (SSNO(-)) targets the Keap-1/Nrf2 redox system.
Nitric oxide (NO), hydrogen sulfide and polysulfides have been proposed to contribute to redox signaling by activating the Keap-1/Nrf2 stress response system. Nitrosopersulfide (SSNO(-)) recently emerged as a bioactive product of the chemical interaction of NO or nitrosothiols with sulfide; upon decomposition it generates polysulfides and free NO, triggering the activation of soluble guanylate cyclase, inducing blood vessel relaxation in vitro and lowering blood pressure in vivo. Whether SSNO(-) itself interacts with the Keap-1/Nrf2 system is unknown. We therefore sought to investigate the ability of SSNO(-) to activate Nrf2-dependent processes in human vascular endothelial cells, and to compare the pharmacological effects of SSNO(-) with those of its precursors NO and sulfide at multiple levels of target engagement. We here demonstrate that SSNO(-) strongly increases Nrf2 nuclear levels, Nrf2-binding activity and transactivation activity, thereby increasing mRNA expression of Hmox-1, the gene encoding for heme oxygenase 1, without adversely affecting cell viability. Under all conditions, SSNO(-) appeared to be more potent than its parent compounds, NO and sulfide. SSNO(-)-induced Nrf2 transactivation activity was abrogated by either NO scavenging with cPTIO or inhibition of thiol sulfuration by high concentrations of cysteine, implying a role for both persulfides/polysulfides and NO in SSNO(-) mediated Nrf2 activation. Taken together, our studies demonstrate that the Keap-1/Nrf2 redox system is a biological target of SSNO(-), enriching the portfolio of bioactivity of this vasoactive molecule to also engage in the regulation of redox signaling processes. The latter suggests a possible role as messenger and/or mediator in cellular sensing and adaptations processes.
1043-6618
1-44
Cortese-Krott, Miriam M.
7dc9b44c-847c-4196-8866-a3cc0c1dc357
Pullmann, David
6d1d206f-4c7d-4bd6-a29c-966f1f421999
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd
Cortese-Krott, Miriam M.
7dc9b44c-847c-4196-8866-a3cc0c1dc357
Pullmann, David
6d1d206f-4c7d-4bd6-a29c-966f1f421999
Feelisch, Martin
8c1b9965-8614-4e85-b2c6-458a2e17eafd

Cortese-Krott, Miriam M., Pullmann, David and Feelisch, Martin (2016) Nitrosopersulfide (SSNO(-)) targets the Keap-1/Nrf2 redox system. Pharmacological Research, 1-44. (doi:10.1016/j.phrs.2016.09.022). (PMID:27663261)

Record type: Article

Abstract

Nitric oxide (NO), hydrogen sulfide and polysulfides have been proposed to contribute to redox signaling by activating the Keap-1/Nrf2 stress response system. Nitrosopersulfide (SSNO(-)) recently emerged as a bioactive product of the chemical interaction of NO or nitrosothiols with sulfide; upon decomposition it generates polysulfides and free NO, triggering the activation of soluble guanylate cyclase, inducing blood vessel relaxation in vitro and lowering blood pressure in vivo. Whether SSNO(-) itself interacts with the Keap-1/Nrf2 system is unknown. We therefore sought to investigate the ability of SSNO(-) to activate Nrf2-dependent processes in human vascular endothelial cells, and to compare the pharmacological effects of SSNO(-) with those of its precursors NO and sulfide at multiple levels of target engagement. We here demonstrate that SSNO(-) strongly increases Nrf2 nuclear levels, Nrf2-binding activity and transactivation activity, thereby increasing mRNA expression of Hmox-1, the gene encoding for heme oxygenase 1, without adversely affecting cell viability. Under all conditions, SSNO(-) appeared to be more potent than its parent compounds, NO and sulfide. SSNO(-)-induced Nrf2 transactivation activity was abrogated by either NO scavenging with cPTIO or inhibition of thiol sulfuration by high concentrations of cysteine, implying a role for both persulfides/polysulfides and NO in SSNO(-) mediated Nrf2 activation. Taken together, our studies demonstrate that the Keap-1/Nrf2 redox system is a biological target of SSNO(-), enriching the portfolio of bioactivity of this vasoactive molecule to also engage in the regulation of redox signaling processes. The latter suggests a possible role as messenger and/or mediator in cellular sensing and adaptations processes.

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Accepted/In Press date: 19 September 2016
e-pub ahead of print date: 20 September 2016
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 400897
URI: https://eprints.soton.ac.uk/id/eprint/400897
ISSN: 1043-6618
PURE UUID: 3229647a-d596-47e8-9fc9-d24236153cc4
ORCID for Martin Feelisch: ORCID iD orcid.org/0000-0003-2320-1158

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Date deposited: 28 Sep 2016 15:44
Last modified: 10 Dec 2019 01:37

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