H2S is an endothelium-derived hyperpolarizing factor

摘要

Aims: Endothelium-dependent vasorelaxation is mediated by endothelium-derived relaxing factor and endothelium-derived hyperpolarizing factor (EDHF). However, the molecular entity of EDHF remains unclear. The present study examined whether hydrogen sulfide (H2S) acts as EDHF and how H2S mediates EDHF pathways from endothelial origination to downstream target of smooth muscle cells (SMCs). Results: We found that knocking-out the expression of cystathionine γ-lyase (CSE) in mice (CSE-knockout [KO]) elevated resting-membrane-potential of SMCs and eliminated methacholine-induced endothelium-dependent relaxation of mesenteric arteries, but not that of aorta. Methacholine, a cholinergic-muscarinic agonist, hyperpolarized SMC in endothelium-intact mesenteric arteries from wide-type mice. This effect was inhibited by muscarinic antagonist (atropine) or the co-application of charybdotoxin and apamin, which blocked intermediate- and small-conductance KCa (IKCa and SKCa) channels, or abolished in CSE-KO mice. Supplementation of exogenous H2S hyperpolarized vascular SMCs and endothelial cells from wide-type and CSE-KO mice. Both methacholine and H2S induced greater SMC hyperpolarization of female wide-type mesenteric arteries than that of male ones. H 2S-induced hyperpolarization is blocked by -SH oxidants and -SSH inhibitor. The expression of SK2.3 but not IK3.1 channel in vascular tissues was increased by H2S and decreased by CSE inhibitor or CSE gene KO. Innovation and Conclusions: Taken together, H 2S is an EDHF. The identification of H2S as an EDHF will not only solve one of the long-lasting perplexing puzzles for the mechanisms underlying endothelium-dependent vasorelaxation, but also shed light on potential therapeutic effects of H2S on pathological abnormalities in peripheral resistance arteries.