Hydrogen sulfide as endothelium-derived hyperpolarizing factor sulfhydrates potassium channels.
Hydrogen sulfide as endothelium-derived hyperpolarizing factor sulfhydrates potassium channels.
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DOI：
10.1161/circresaha.111.240242
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发表时间：
2011-11-11
影响因子：
20.1
通讯作者：
Snyder SH
中科院分区：
文献类型：
--
作者：
Mustafa AK;Sikka G;Gazi SK;Steppan J;Jung SM;Bhunia AK;Barodka VM;Gazi FK;Barrow RK;Wang R;Amzel LM;Berkowitz DE;Snyder SH
一氧化氮是经典的内皮源性松弛因子(EDRF)，通过环GMP和钙离子发挥作用，对膜电位无明显影响。EDRF活性的一个主要成分来自超极化，被称为内皮衍生超极化因子(EDHF)。硫化氢(H_2S)是一种重要的EDRF，因为缺乏其生物合成酶-胱硫醚γ-裂解酶(CSE)的小鼠表现出明显的高血压，对乙酰胆碱的血管松弛反应不足。本研究的目的是确定硫化氢是否是一种主要的生理性EDHF。我们现在表明，硫化氢是一种主要的EDHF，因为在CSE缺失的小鼠的血管中，超极化实际上是被消除的。H_2S通过共价修饰(硫水化)ATP敏感的钾通道起作用，因为突变的硫水化位置可防止H_2S引起的超极化。内皮中间电导(IKCa)和小电导(SKCa)钾通道部分介导了H_2S对格列本脲不敏感的H_2S引起的血管松弛的抑制作用。硫化氢是一种主要的EDHF，通过半胱氨酸S-硫酸盐水合作用激活三磷酸腺苷敏感钾通道、中电导钾通道和小电导钾通道，引起血管内皮细胞和平滑肌细胞超极化和血管松弛。由于EDHF活性是许多血管床中血管松弛的主要决定因素，影响硫化氢生物合成的药物提供了治疗潜力。
Nitric oxide, the classic endothelial derived relaxing factor (EDRF), acts via cyclic GMP and calcium without notably affecting membrane potential. A major component of EDRF activity derives from hyperpolarization and is termed endothelial derived hyperpolarizing factor (EDHF). Hydrogen sulfide (H2S) is a prominent EDRF, since mice lacking its biosynthetic enzyme, cystathionine γ-lyase (CSE), display pronounced hypertension with deficient vasorelaxant responses to acetylcholine. The purpose of this study is to determine if H2S is a major physiologic EDHF. We now show that H2S is a major EDHF, as 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. 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. As EDHF activity is a principal determinant of vasorelaxation in numerous vascular beds, drugs influencing H2S biosynthesis offer therapeutic potential.