Hydrogen peroxide induces vasorelaxation by enhancing 4-aminopyridine-sensitive Kv currents through S-glutathionylation

被引:48
作者
Park, Sang Woong [1 ]
Noh, Hyun Ju [1 ]
Sung, Dong Jun [2 ]
Kim, Jae Gon [3 ,4 ]
Kim, Jeong Min [1 ]
Ryu, Shin-Young [5 ,6 ]
Kang, KyeongJin [7 ]
Kim, Bokyung [1 ]
Bae, Young Min [1 ]
Cho, Hana [3 ,4 ]
机构
[1] Konkuk Univ, Sch Med, Dept Physiol, Res Inst Med Sci,Inst Funct Genom, Choongju 380701, South Korea
[2] Konkuk Univ, Div Sport Sci, Coll Sci & Technol, Choongju 380701, South Korea
[3] Sungkyunkwan Univ, Dept Physiol, Suwon, South Korea
[4] Sungkyunkwan Univ, Sch Med, Samsung Biomed Res Inst, Suwon, South Korea
[5] Seoul Natl Univ, Dept Physiol, Seoul, South Korea
[6] Seoul Natl Univ, Coll Med, Biomembrane Plast Res Ctr, Seoul, South Korea
[7] Sungkyunkwan Univ, Dept Anat & Cell Biol, Sch Med, Suwon, South Korea
来源
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY | 2015年 / 467卷 / 02期
基金
新加坡国家研究基金会;
关键词
H2O2; Kv channel; Mesenteric artery; S-glutathionylation; Oxidative stress; SMOOTH-MUSCLE-CELLS; RAT MESENTERIC-ARTERY; PROTEIN-KINASE-C; ENDOTHELIUM-DEPENDENT HYPERPOLARIZATION; HUMAN CORONARY ARTERIOLES; HUMAN DUCTUS-ARTERIOSUS; GATED K+ CHANNELS; NITRIC-OXIDE; ATP CHANNEL; RESISTANCE ARTERIES;
D O I
10.1007/s00424-014-1513-3
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
Hydrogen peroxide (H2O2) is an endothelium-derived hyperpolarizing factor. Since opposing vasoactive effects have been reported for H2O2 depending on the vascular bed and experimental conditions, this study was performed to assess whether H2O2 acts as a vasodilator in the rat mesenteric artery and, if so, to determine the underlying mechanisms. H2O2 elicited concentration-dependent relaxation in mesenteric arteries precontracted with norepinephrine. The vasodilatory effect of H2O2 was reversed by treatment with dithiothreitol. H2O2-elicited vasodilation was significantly reduced by blocking 4-aminopyridine (4-AP)-sensitive Kv channels, but it was resistant to blockers of big-conductance Ca2+-activated K+ channels and inward rectifier K+ channels. A patch-clamp study in mesenteric arterial smooth muscle cells (MASMCs) showed that H2O2 increased Kv currents in a concentration-dependent manner. H2O2 speeded up Kv channel activation and shifted steady state activation to hyperpolarizing potentials. Similar channel activation was seen with oxidized glutathione (GSSG). The H2O2-mediated channel activation was prevented by glutathione reductase. Consistent with S-glutathionylation, streptavidin pull-down assays with biotinylated glutathione ethyl ester showed incorporation of glutathione (GSH) in the Kv channel proteins in the presence of H2O2. Interestingly, conditions of increased oxidative stress within MASMCs impaired the capacity of H2O2 to stimulate Kv channels. Not only was the H2O2 stimulatory effect much weaker, but the inhibitory effect of H2O2 was unmasked. These data suggest that H2O2 activates 4-AP-sensitive Kv channels, possibly through S-glutathionylation, which elicits smooth muscle relaxation in rat mesenteric arteries. Furthermore, our results support the idea that the basal redox status of MASMCs determines the response of Kv currents to H2O2.
引用
收藏
页码:285 / 297
页数:13
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