Hydrogen sulfide, an enhancer of vascular nitric oxide signaling

Mechanisms and implications

    Research output: Contribution to journalArticle

    34 Citations (Scopus)

    Abstract

    Nitric oxide (NO) vascular signaling has long been considered an independent, self-sufficient pathway. However, recent data indicate that the novel gaseous mediator, hydrogen sulfide (H2S), serves as an essential enhancer of vascular NO signaling. The current article overviews the multiple levels at which this enhancement takes place. The first level of interaction relates to the formation of biologically active hybrid S/N species and the H2S-induced stimulation of NO release from its various stable “pools” (e.g., nitrite). The next interactions occur on the level of endothelial calcium mobilization and PI3K/Akt signaling, increasing the specific activity of endothelial NO synthase (eNOS). The next level of interaction occurs on eNOS itself; H2S directly interacts with the enzyme: sulfhydration of critical cysteines stabilizes it in its physiological, dimeric state, thereby optimizing eNOS-derived NO production and minimizing superoxide formation. Yet another level of interaction, further downstream, occurs at the level of soluble guanylate cyclase (sGC): H2S stabilizes sGC in its NO-responsive, physiological, reduced form. Further downstream, H2S inhibits the vascular cGMP phosphodiesterase (PDE5), thereby prolonging the biological half-life of cGMP. Finally, H2S-derived polysulfides directly activate cGMP-dependent protein kinase (PKG). Taken together, H2S emerges an essential endogenous enhancer of vascular NO signaling, contributing to vasorelaxation and angiogenesis. The functional importance of the H2S/NO cooperative interactions is highlighted by the fact that H2S loses many of its beneficial cardiovascular effects when eNOS is inactive.

    Original languageEnglish (US)
    Pages (from-to)C3-C15
    JournalAmerican Journal of Physiology - Cell Physiology
    Volume312
    Issue number1
    DOIs
    StatePublished - 2017

    Fingerprint

    Hydrogen Sulfide
    Blood Vessels
    Nitric Oxide
    Nitric Oxide Synthase
    Gasotransmitters
    Type 5 Cyclic Nucleotide Phosphodiesterases
    Cyclic GMP-Dependent Protein Kinases
    Nitric Oxide Synthase Type III
    Nitrites
    Phosphatidylinositol 3-Kinases
    Vasodilation
    Superoxides
    Cysteine
    Half-Life
    Calcium
    Enzymes

    Keywords

    • Angiogenesis
    • CGMP
    • Hydrogen sulfide
    • Nitric oxide
    • Vascular

    ASJC Scopus subject areas

    • Physiology
    • Cell Biology

    Cite this

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    title = "Hydrogen sulfide, an enhancer of vascular nitric oxide signaling: Mechanisms and implications",
    abstract = "Nitric oxide (NO) vascular signaling has long been considered an independent, self-sufficient pathway. However, recent data indicate that the novel gaseous mediator, hydrogen sulfide (H2S), serves as an essential enhancer of vascular NO signaling. The current article overviews the multiple levels at which this enhancement takes place. The first level of interaction relates to the formation of biologically active hybrid S/N species and the H2S-induced stimulation of NO release from its various stable “pools” (e.g., nitrite). The next interactions occur on the level of endothelial calcium mobilization and PI3K/Akt signaling, increasing the specific activity of endothelial NO synthase (eNOS). The next level of interaction occurs on eNOS itself; H2S directly interacts with the enzyme: sulfhydration of critical cysteines stabilizes it in its physiological, dimeric state, thereby optimizing eNOS-derived NO production and minimizing superoxide formation. Yet another level of interaction, further downstream, occurs at the level of soluble guanylate cyclase (sGC): H2S stabilizes sGC in its NO-responsive, physiological, reduced form. Further downstream, H2S inhibits the vascular cGMP phosphodiesterase (PDE5), thereby prolonging the biological half-life of cGMP. Finally, H2S-derived polysulfides directly activate cGMP-dependent protein kinase (PKG). Taken together, H2S emerges an essential endogenous enhancer of vascular NO signaling, contributing to vasorelaxation and angiogenesis. The functional importance of the H2S/NO cooperative interactions is highlighted by the fact that H2S loses many of its beneficial cardiovascular effects when eNOS is inactive.",
    keywords = "Angiogenesis, CGMP, Hydrogen sulfide, Nitric oxide, Vascular",
    author = "Csaba Szabo",
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    T1 - Hydrogen sulfide, an enhancer of vascular nitric oxide signaling

    T2 - Mechanisms and implications

    AU - Szabo, Csaba

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    AB - Nitric oxide (NO) vascular signaling has long been considered an independent, self-sufficient pathway. However, recent data indicate that the novel gaseous mediator, hydrogen sulfide (H2S), serves as an essential enhancer of vascular NO signaling. The current article overviews the multiple levels at which this enhancement takes place. The first level of interaction relates to the formation of biologically active hybrid S/N species and the H2S-induced stimulation of NO release from its various stable “pools” (e.g., nitrite). The next interactions occur on the level of endothelial calcium mobilization and PI3K/Akt signaling, increasing the specific activity of endothelial NO synthase (eNOS). The next level of interaction occurs on eNOS itself; H2S directly interacts with the enzyme: sulfhydration of critical cysteines stabilizes it in its physiological, dimeric state, thereby optimizing eNOS-derived NO production and minimizing superoxide formation. Yet another level of interaction, further downstream, occurs at the level of soluble guanylate cyclase (sGC): H2S stabilizes sGC in its NO-responsive, physiological, reduced form. Further downstream, H2S inhibits the vascular cGMP phosphodiesterase (PDE5), thereby prolonging the biological half-life of cGMP. Finally, H2S-derived polysulfides directly activate cGMP-dependent protein kinase (PKG). Taken together, H2S emerges an essential endogenous enhancer of vascular NO signaling, contributing to vasorelaxation and angiogenesis. The functional importance of the H2S/NO cooperative interactions is highlighted by the fact that H2S loses many of its beneficial cardiovascular effects when eNOS is inactive.

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