Hydrogen sulfide preserves endothelial nitric oxide synthase function by inhibiting proline-rich kinase 2: Implications for cardiomyocyte survival and cardioprotection

Sofia Iris Bibli, Csaba Szabo, Athanasia Chatzianastasiou, Bert Luck, Sven Zukunft, Ingrid Fleming, Andreas Papapetropoulos

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    Hydrogen sulfide (H2S) exhibits beneficial effects in the cardiovascular system,many of which depend on nitric oxide (NO). Proline-rich tyrosine kinase 2 (PYK2), a redox-sensitive tyrosine kinase, directly phosphorylates and inhibits endothelial NO synthase (eNOS). We investigated the ability of H2S to relieve PYK2-mediated eNOS inhibition and evaluated the importance of the H2S/PYK2/eNOS axis on cardiomyocyte injury in vitro and in vivo. Exposure of H9c2 cardiomyocytes to H2O2 or pharmacologic inhibition of H2S production increased PYK2 (Y402) and eNOS (Y656) phosphorylation. These effects were blocked by treatment with Na2S or by overexpression of cystathionine γ-lyase (CSE). In addition, PYK2 overexpression reduced eNOS activity in a H2S-reversible manner. The viability of cardiomyocytes exposed to H2 O2 was reduced and declined further after the inhibition of H2S production. PYK2 downregulation, L-cysteine supplementation, or CSE overexpression alleviated the effects of H2O2 on H9c2 cardiomyocyte survival. Moreover, H2S promoted PYK2 sulfhydration and inhibited its activity. In vivo, H2S administration reduced reactive oxygen species levels, as well as PYK2 (Y402) and eNOS (Y656) phosphorylation. Pharmacologic blockade of PYK2 or inhibition of PYK2 activation by Na2S reduced myocardial infarct size in mice. Coadministration of a PYK2 inhibitor and Na2S did not result in additive effects on infarct size. We conclude that H2S relieves the inhibitory effect of PYK2 on eNOS, allowing the latter to produce greater amounts of NO, thereby affording cardioprotection. Our results unravel the existence of a novel H2S-NO interaction and identify PYK2 as a crucial target for the protective effects of H2S under conditions of oxidative stres.

    Original languageEnglish (US)
    Pages (from-to)718-730
    Number of pages13
    JournalMolecular Pharmacology
    Issue number6
    StatePublished - Dec 1 2017


    ASJC Scopus subject areas

    • Molecular Medicine
    • Pharmacology

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