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 nuclear levels, binding activity and transactivation activity of Nrf2, 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.
Cardiovascular Research Laboratory, Department of Cardiology, Pneumology and Vascular Medicine, Medical Faculty, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany. Electronic address: miriam.cortese@uni-duesseldorf.de.
Miriam M
MM
Cortese-Krott
Cardiovascular Research Laboratory, Department of Cardiology, Pneumology and Vascular Medicine, Medical Faculty, Heinrich Heine University of Düsseldorf, Düsseldorf, Germany.
David
D
Pullmann
Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Tremona Road, Southampton, United Kingdom. Electronic address: m.feelisch@soton.ac.uk.
Martin
M
Feelisch
D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D051547:Heme Oxygenase-1 / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006862:Hydrogen Sulfide / Q000494:pharmacology; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D009602:Nitrosamines / Q000494:pharmacology*; D010084:Oxidation-Reduction / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D013440:Sulfides / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects
C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009602:Nitrosamines; D012333:RNA, Messenger; D013438:Sulfhydryl Compounds; D013440:Sulfides; D009569:Nitric Oxide; C002743:N-nitrosopiperidine; C032915:polysulfide; D051547:Heme Oxygenase-1; D006862:Hydrogen Sulfide
NO and H(2)S cross talk; Nitrosopersulfide; Nitroxyl; Persulfide; Polysulfide; Redox sensing