Cardioprotection by H2S Donors: Nitric Oxide-Dependent and -Independent Mechanisms

Athanasia Chatzianastasiou, Sofia Iris Bibli, Ioanna Andreadou, Panagiotis Efentakis, Nina Kaludercic, Mark E. Wood, Matthew Whiteman, Fabio Di Lisa, Andreas Daiber, Vangelis G. Manolopoulos, Csaba Szabo, D. Andreas Papapetropoulos

    Research output: Contribution to journalArticle

    29 Citations (Scopus)

    Abstract

    Hydrogen sulfide (H2S) is a signaling molecule with protective effects in the cardiovascular system. To harness the therapeutic potential of H2S, a number of donors have been developed. The present study compares the cardioprotective actions of representative H2S donors from different classes and studies their mechanisms of action inmyocardial injury in vitro and in vivo. Exposure of cardiomyocytes to H2O2 led to significant cytotoxicity, which was inhibited by sodium sulfide (Na2S), thiovaline (TV), GYY4137 [morpholin-4-ium 4 methoxyphenyl(morpholino) phosphinodithioate], and AP39 [(10-oxo-10-(4-(3-thioxo-3H-1,2-dithiol5yl)- phenoxy)decyl) triphenylphospho-nium bromide]. Inhibition of nitric oxide (NO) synthesis prevented the cytoprotective effects of Na2S and TV, but not GYY4137 and AP39, against H2O2-induced cardiomyocyte injury. Mice subjected to left anterior descending coronary ligation were protected from ischemia-reperfusion injury by the H2S donors tested. Inhibition of nitric oxide synthase (NOS) in vivo blocked only the beneficial effect of Na2S. Moreover, Na2S, but not AP39, administration enhanced the phosphorylation of endothelial NOS and vasodilator-associated phosphoprotein. Both Na2S and AP39 reduced infarct size in mice lacking cyclophilin-D (CypD), a modulator of the mitochondrial permeability transition pore (PTP). Nevertheless, only AP39 displayed a direct effect on mitochondria by increasing the mitochondrial Ca2+ retention capacity, which is evidence of decreased propensity to undergo permeability transition. We conclude that although all the H2S donors we tested limited infarct size, the pathways involved were not conserved. Na2S had no direct effects on PTP opening, and its action was nitric oxide dependent. In contrast, the cardioprotection exhibited by AP39 could result from a direct inhibitory effect on PTP acting at a site different than CypD.

    Original languageEnglish (US)
    Pages (from-to)431-440
    Number of pages10
    JournalJournal of Pharmacology and Experimental Therapeutics
    Volume358
    Issue number3
    DOIs
    StatePublished - Sep 1 2016

    Fingerprint

    Nitric Oxide Donors
    Permeability
    Cardiac Myocytes
    Nitric Oxide
    Hydrogen Sulfide
    Nitric Oxide Synthase Type III
    Phosphoproteins
    Wounds and Injuries
    Cardiovascular System
    sodium sulfide
    Reperfusion Injury
    Bromides
    Vasodilator Agents
    Nitric Oxide Synthase
    Ligation
    Mitochondria
    Phosphorylation
    GYY 4137

    ASJC Scopus subject areas

    • Medicine(all)
    • Molecular Medicine
    • Pharmacology

    Cite this

    Chatzianastasiou, A., Bibli, S. I., Andreadou, I., Efentakis, P., Kaludercic, N., Wood, M. E., ... Papapetropoulos, D. A. (2016). Cardioprotection by H2S Donors: Nitric Oxide-Dependent and -Independent Mechanisms. Journal of Pharmacology and Experimental Therapeutics, 358(3), 431-440. https://doi.org/10.1124/jpet.116.235119

    Cardioprotection by H2S Donors : Nitric Oxide-Dependent and -Independent Mechanisms. / Chatzianastasiou, Athanasia; Bibli, Sofia Iris; Andreadou, Ioanna; Efentakis, Panagiotis; Kaludercic, Nina; Wood, Mark E.; Whiteman, Matthew; Lisa, Fabio Di; Daiber, Andreas; Manolopoulos, Vangelis G.; Szabo, Csaba; Papapetropoulos, D. Andreas.

    In: Journal of Pharmacology and Experimental Therapeutics, Vol. 358, No. 3, 01.09.2016, p. 431-440.

    Research output: Contribution to journalArticle

    Chatzianastasiou, A, Bibli, SI, Andreadou, I, Efentakis, P, Kaludercic, N, Wood, ME, Whiteman, M, Lisa, FD, Daiber, A, Manolopoulos, VG, Szabo, C & Papapetropoulos, DA 2016, 'Cardioprotection by H2S Donors: Nitric Oxide-Dependent and -Independent Mechanisms', Journal of Pharmacology and Experimental Therapeutics, vol. 358, no. 3, pp. 431-440. https://doi.org/10.1124/jpet.116.235119
    Chatzianastasiou A, Bibli SI, Andreadou I, Efentakis P, Kaludercic N, Wood ME et al. Cardioprotection by H2S Donors: Nitric Oxide-Dependent and -Independent Mechanisms. Journal of Pharmacology and Experimental Therapeutics. 2016 Sep 1;358(3):431-440. https://doi.org/10.1124/jpet.116.235119
    Chatzianastasiou, Athanasia ; Bibli, Sofia Iris ; Andreadou, Ioanna ; Efentakis, Panagiotis ; Kaludercic, Nina ; Wood, Mark E. ; Whiteman, Matthew ; Lisa, Fabio Di ; Daiber, Andreas ; Manolopoulos, Vangelis G. ; Szabo, Csaba ; Papapetropoulos, D. Andreas. / Cardioprotection by H2S Donors : Nitric Oxide-Dependent and -Independent Mechanisms. In: Journal of Pharmacology and Experimental Therapeutics. 2016 ; Vol. 358, No. 3. pp. 431-440.
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    abstract = "Hydrogen sulfide (H2S) is a signaling molecule with protective effects in the cardiovascular system. To harness the therapeutic potential of H2S, a number of donors have been developed. The present study compares the cardioprotective actions of representative H2S donors from different classes and studies their mechanisms of action inmyocardial injury in vitro and in vivo. Exposure of cardiomyocytes to H2O2 led to significant cytotoxicity, which was inhibited by sodium sulfide (Na2S), thiovaline (TV), GYY4137 [morpholin-4-ium 4 methoxyphenyl(morpholino) phosphinodithioate], and AP39 [(10-oxo-10-(4-(3-thioxo-3H-1,2-dithiol5yl)- phenoxy)decyl) triphenylphospho-nium bromide]. Inhibition of nitric oxide (NO) synthesis prevented the cytoprotective effects of Na2S and TV, but not GYY4137 and AP39, against H2O2-induced cardiomyocyte injury. Mice subjected to left anterior descending coronary ligation were protected from ischemia-reperfusion injury by the H2S donors tested. Inhibition of nitric oxide synthase (NOS) in vivo blocked only the beneficial effect of Na2S. Moreover, Na2S, but not AP39, administration enhanced the phosphorylation of endothelial NOS and vasodilator-associated phosphoprotein. Both Na2S and AP39 reduced infarct size in mice lacking cyclophilin-D (CypD), a modulator of the mitochondrial permeability transition pore (PTP). Nevertheless, only AP39 displayed a direct effect on mitochondria by increasing the mitochondrial Ca2+ retention capacity, which is evidence of decreased propensity to undergo permeability transition. We conclude that although all the H2S donors we tested limited infarct size, the pathways involved were not conserved. Na2S had no direct effects on PTP opening, and its action was nitric oxide dependent. In contrast, the cardioprotection exhibited by AP39 could result from a direct inhibitory effect on PTP acting at a site different than CypD.",
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