Resveratrol stimulates nitric oxide production by increasing estrogen receptor α-Src-caveolin-1 interaction and phosphorylation in human umbilical vein endothelial cells
Resveratrol stimulates nitric oxide production by increasing estrogen receptor α-Src-caveolin-1 interaction and phosphorylation in human umbilical vein endothelial cells
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DOI：
10.1096/fj.07-103366
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发表时间：
2008-07-01
期刊：
影响因子：
4.8
通讯作者：
Dougherty, Susan M.
中科院分区：
文献类型：
--
作者：
Klinge, Carolyn M.;Wickramasinghe, Nalinie S.;Dougherty, Susan M.
流行病学研究表明，适量饮用红酒可以降低心血管疾病的发病率。白藜芦醇是红酒中的一种多酚化合物，对啮齿动物有心脏保护作用。尽管内皮细胞(EC)研究表明微摩尔白藜芦醇具有不同的生物活性，但这些浓度与生理无关，因为人类口服仅提供短暂的纳摩尔血浆水平。此前，我们报道了纳米白藜芦醇激活牛主动脉内皮细胞ERK1/2信号转导通路。本研究旨在探讨纳米白藜芦醇快速激活人脐静脉内皮细胞内皮型一氧化氮合酶(ENOS)的机制。我们首次报道白藜芦醇增加雌激素受体α(ERα)、小窝蛋白-1(Cav-1)和c-Src之间的相互作用，并增加Cav-1、c-Src和eNOS的磷酸化。脂筏干扰剂β-甲基环糊精或Gα抑制剂百日咳毒素可阻断白藜芦醇和E-2诱导的eNOS激活和NO的产生。SiRNA耗尽内源性ERα而不是ERβ可减弱白藜芦醇和E2诱导的ERK1/2、Src和eNOS的磷酸化。我们的数据表明，纳米白藜芦醇诱导ERα-Cav-1-c-SRC相互作用，通过Gα蛋白偶联机制产生NO。这项研究为白藜芦醇在内皮细胞中的有益作用机制提供了重要的新见解。
Epidemiological studies correlate moderate red wine consumption to reduced incidence of cardiovascular disease. Resveratrol is a polyphenolic compound in red wine that has cardioprotective effects in rodents. Although endothelial cell (EC) studies indicate that micromolar resveratrol has diverse biological activities, these concentrations are not physiologically relevant because human oral ingestion provides only brief exposure to nanomolar plasma levels. Previously, we reported that nanomolar resveratrol activated ERK1/2 signaling in bovine aortic ECs (BAECs). The goal of this study was to determine the mechanisms by which nanomolar resveratrol rapidly activates endothelial nitric oxide synthase (eNOS) in human umbilical vein ECs (HUVECs). We report for the first time that resveratrol increased interaction between estrogen receptor alpha (ER alpha), caveolin-1 (Cav-1) and c-Src, and increased phosphorylation of Cav-1, c-Src, and eNOS. Pretreatment with the lipid raft disruptor beta-methyl cyclodextrin or G alpha inhibitor pertussis toxin blocked resveratrol- and E-2-induced eNOS activation and NO production. Depletion of endogenous ER alpha, not ER beta, by siRNA attenuated resveratrol- and E2-induced ERK1/2, Src, and eNOS phosphorylation. Our data demonstrate that nanomolar resveratrol induces ER alpha-Cav-1-c-SRC interaction, resulting in NO production through a G alpha-protein-coupled mechanism. This study provides important new insights into mechanisms for the beneficial effects of resveratrol in ECs.