Regulation of soluble guanylyl cyclase redox state by hydrogen sulfide

Zongmin Zhou, Emil Martin, Iraida Sharina, Iolanda Esposito, Csaba Szabo, Mariarosaria Bucci, Giuseppe Cirino, Andreas Papapetropoulos

    Research output: Contribution to journalArticle

    35 Scopus citations

    Abstract

    Soluble guanylate cyclase (sGC) is a receptor for nitric oxide (NO). Binding of NO to ferrous (Fe2+) 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.

    Original languageEnglish (US)
    Pages (from-to)556-562
    Number of pages7
    JournalPharmacological Research
    Volume111
    DOIs
    StatePublished - Sep 1 2016

    Keywords

    • cGMP
    • HS
    • Nitric oxide
    • ROS
    • sGC activators

    ASJC Scopus subject areas

    • Pharmacology

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  • Cite this

    Zhou, Z., Martin, E., Sharina, I., Esposito, I., Szabo, C., Bucci, M., Cirino, G., & Papapetropoulos, A. (2016). Regulation of soluble guanylyl cyclase redox state by hydrogen sulfide. Pharmacological Research, 111, 556-562. https://doi.org/10.1016/j.phrs.2016.06.029