Hydrogen Sulfide as Endothelial Derived Hyperpolarizing Factor Sulfhydrates Potassium Channels
By A. Mustafa, G. Sikka, Sadia K. Gazi, J. Steppan, S. Jung, A. Bhunia, V. Barodka, Farah K Gazi, R. Barrow, Rui Wang and 3 more. Circulation Research, 2011
620 citations recorded by the source corpus.
Rationale: Nitric oxide, the classic endothelium-derived relaxing factor (EDRF), acts through cyclic GMP and calcium without notably affecting membrane potential. A major component of EDRF activity derives from hyperpolarization and is termed endothelium-derived hyperpolarizing factor (EDHF). Hydrogen sulfide (H2S) is a prominent EDRF, since mice lacking its biosynthetic enzyme, cystathionine &ggr;-lyase (CSE), display pronounced hypertension with deficient vasorelaxant responses to acetylcholine. Objective: The purpose of this study was to determine if H2S is a major physiological EDHF. Methods and Results: We now show that H2S is a major EDHF because in blood vessels of CSE-deleted mice, hyperpolarization is virtually abolished. H2S acts by covalently modifying (sulfhydrating) the ATP-sensitive potassium channel, as mutating the site of sulfhydration prevents H2S-elicited hyperpolarization. The endothelial intermediate conductance (IKCa) and small conductance (SKCa) potassium channels mediate in part the effects of H2S, as selective IKCa and SKCa channel inhibitors, charybdotoxin and apamin, inhibit glibenclamide-insensitive, H2S-induced vasorelaxation. Conclusions: H2S is a major EDHF that causes vascular endothelial and smooth muscle cell hyperpolarization and vasorelaxation by activating the ATP-sensitive, intermediate conductance and small conductance potassium channels through cysteine S-sulfhydration. Because EDHF activity is a principal determinant of vasorelaxation in numerous vascular beds, drugs influencing H2S biosynthesis offer therapeutic potential.
Subfields: Biochemistry, Physiology
View Paper: https://www.semanticscholar.org/paper/3da674333786d890982d73bcb04465ccea4e626a
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Citations in the corpus
- Hydrogen sulfide and nitric oxide are mutually dependent in the regulation of angiogenesis and endothelium-dependent vasorelaxation (2012, background): “These responses likely involve parallel pathways of H2S-induced vasorelaxation, such as KATP channels (24, 25) and other types of potassium channels and the ion exchangers (17).”
- Tumor-derived hydrogen sulfide, produced by cystathionine-β-synthase, stimulates bioenergetics, cell proliferation, and angiogenesis in colon cancer (2013, background): “(2012) Detoxification of H(2)S by differentiated colonic epithelial cells: Implication of the sulfide oxidizing unit and of the cell respiratory capacity.”
- Physiological implications of hydrogen sulfide: a whiff exploration that blossomed. (2012, methodology): “1 subunit of KATP channels heterologously expressed in HEK-293 cells and IKCa channels in primary human aortic endothelial cells (421), detected by a modified biotin switch assay.”