Hydrogen peroxide potentiates the EDHF phenomenon by promoting endothelial Ca2+ mobilization
Hydrogen peroxide potentiates the EDHF phenomenon by promoting endothelial Ca2+ mobilization
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DOI：
10.1161/atvbaha.108.172692
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发表时间：
2008-10-01
影响因子：
8.7
通讯作者：
Griffith, Tudor M.
中科院分区：
文献类型：
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作者：
Edwards, David H.;Li, Yiwen;Griffith, Tudor M.
目的 -本研究的目的是检验 H(2)O(2) 通过动员内皮 Ca(2+) 储备促进 EDHF 现象的假设。方法和结果 -用兔髂动脉进行肌动描记研究表明，SERCA 抑制剂环吡阿尼酸 (CPA) 引起的 EDHF 型松弛需要激活 K(Ca) 通道，并通过外源性 H(2)O(2) 和硫醇增强氧化剂硫柳汞。与次最大浓度的 CPA 预孵育揭示了外源 H(2)O(2) 刺激对 KCa 通道阻断敏感的 EDHF 型反应的能力。使用 Fura-2 和 Mag-fluo-4 对兔主动脉瓣内皮细胞的胞浆和内质网 [Ca(2+)] 进行成像，结果表明，H(2)O(2) 和硫柳汞（使 InsP(3) 受体敏感）均增强 CPA 诱发的 Ca(2+) 从储备中的释放，并且 H(2)O(2) 的增强作用被抑制细胞渗透性硫醇还原剂谷胱甘肽单乙酯。 CPA 引起的松弛被外源性过氧化氢酶减弱，并被过氧化氢酶抑制剂 3-氨基三唑增强，并被连接蛋白模拟肽 (43)Gap26 消除，该肽通过由连接蛋白 43 构建的间隙连接中断细胞间通讯。结论 - H(2)O(2) 可以通过增强内皮细胞 Ca(2+) 的释放来增强 EDHF 型松弛储存，可能通过 InsP(3) 受体的氧化还原修饰，导致超极化内皮 KCa 通道的开放和电紧张介导的松弛反应。
Objective -The purpose of this study was to test the hypothesis that H(2)O(2) contributes to the EDHF phenomenon by mobilizing endothelial Ca(2+) stores.Methods and Results -Myograph studies with rabbit iliac arteries demonstrated that EDHF-type relaxations evoked by the SERCA inhibitor cyclopiazonic acid (CPA) required activation of K(Ca) channels and were potentiated by exogenous H(2)O(2) and the thiol oxidant thimerosal. Preincubation with a submaximal concentration of CPA unmasked an ability of exogenous H(2)O(2) to stimulate an EDHF-type response that was sensitive to KCa channel blockade. Imaging of cytosolic and endoplasmic reticulum [Ca(2+)] in rabbit aortic valve endothelial cells with Fura-2 and Mag-fluo-4 demonstrated that H(2)O(2) and thimerosal, which sensitizes the InsP(3) receptor, both enhanced CPA-evoked Ca(2+) release from stores, and that the potentiating effect of H(2)O(2) was suppressed by the cell-permeant thiol reductant glutathione monoethylester. CPA-evoked relaxations were attenuated by exogenous catalase and potentiated by the catalase inhibitor 3-aminotriazole, and were abolished by the connexin-mimetic peptide (43)Gap26, which interrupts intercellular communication via gap junctions constructed from connexin 43.Conclusions - H(2)O(2) can enhance EDHF-type relaxations by potentiating Ca(2+) release from endothelial stores, probably via redox modification of the InsP(3) receptor, leading to the opening of hyperpolarizing endothelial KCa channels and an electrotonically-mediated relaxant response.