title: Regulation of soluble guanylyl cyclase redox state by hydrogen sulfide.
abstract: Soluble guanylate cyclase (sGC) is a receptor for nitric oxide (NO). Binding of NO to ferrous (Fe(2+)) heme increases its catalytic activity, leading to the production of cGMP from GTP. Hydrogen sulfide (H2S) is a signaling molecule that exerts both direct and indirect anti-oxidant effects. In the present, study we aimed to determine whether H2S could regulate sGC redox state and affect its responsiveness to NO-releasing agents and sGC activators. Using cultured rat aortic smooth muscle cells, we observed that treatment with H2S augmented the response to the NO donor DEA/NO, while attenuating the response to the heme-independent activator BAY58-2667 that targets oxidized sGC. Similarly, overexpression of H2S-synthesizing enzyme cystathionine-γ lyase reduced the ability of BAY58-2667 to promote cGMP accumulation. In experiments with phenylephrine-constricted mouse aortic rings, treatment with rotenone (a compound that increases ROS production), caused a rightward shift of the DEA/NO concentration-response curve, an effect partially restored by H2S. When rings were pre-treated with H2S, the concentration-response curve to BAY 58-2667 shifted to the right. Using purified recombinant human sGC, we observed that treatment with H2S converted ferric to ferrous sGC enhancing NO-donor-stimulated sGC activity and reducing BAY 58-2667-triggered cGMP formation. The present study identified an additional mechanism of cross-talk between the NO and H2S pathways at the level of redox regulation of sGC. Our results provide evidence that H2S reduces sGC heme Fe, thus, facilitating NO-mediated cellular signaling events.
authors.affiliation: 1st Department of Critical Care and Pulmonary Services, Faculty of Medicine, National and Kapodistrian University of Athens, Evangelismos Hospital, Greece.
authors.forename: Zongmin
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Division of Cardiology, Department of Internal Medicine, University of Texas Medical School at Houston, TX, USA.
authors.forename: Emil
authors.initials: E
authors.lastname: Martin
authors.affiliation: Division of Cardiology, Department of Internal Medicine, University of Texas Medical School at Houston, TX, USA.
authors.forename: Iraida
authors.initials: I
authors.lastname: Sharina
authors.affiliation: Department of Experimental Pharmacology, Faculty of Pharmacy, University of Naples⿿Federico II, Italy.
authors.forename: Iolanda
authors.initials: I
authors.lastname: Esposito
authors.affiliation: Department of Anesthesiology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabo
authors.affiliation: Department of Experimental Pharmacology, Faculty of Pharmacy, University of Naples⿿Federico II, Italy.
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: Bucci
authors.affiliation: Department of Experimental Pharmacology, Faculty of Pharmacy, University of Naples⿿Federico II, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cirino
authors.affiliation: 1st Department of Critical Care and Pulmonary Services, Faculty of Medicine, National and Kapodistrian University of Athens, Evangelismos Hospital, Greece; Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Greece; Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Greece. Electronic address: apapapet@pharm.uoa.gr.
authors.forename: Andreas
authors.initials: A
authors.lastname: Papapetropoulos
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001565:Benzoates / Q000494:pharmacology; D002478:Cells, Cultured; D003542:Cystathionine gamma-Lyase / Q000378:metabolism; D006418:Heme / Q000378:metabolism*; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D066298:In Vitro Techniques; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010084:Oxidation-Reduction; D010656:Phenylephrine; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D051381:Rats; D000071756:Soluble Guanylyl Cyclase / Q000378:metabolism*
chemical_list: D001565:Benzoates; D020030:Nitric Oxide Donors; D000644:Quaternary Ammonium Compounds; C406802:diethylammonium-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate; D010656:Phenylephrine; D009569:Nitric Oxide; C480588:BAY 58-2667; D006418:Heme; D003542:Cystathionine gamma-Lyase; D000071756:Soluble Guanylyl Cyclase; D006862:Hydrogen Sulfide
keywords: H(2)S; Nitric oxide; ROS; cGMP; sGC activators