Farrerol regulates occludin expression in hydrogen peroxide-induced EA.hy926 cells by modulating ERK1/2 activity
Farrerol regulates occludin expression in hydrogen peroxide-induced EA.hy926 cells by modulating ERK1/2 activity
复制标题
Farrerol 通过调节 ERK1/2 活性来调节过氧化氢诱导的 EA.hy926 细胞中的 occludin 表达。
DOI：
10.1016/j.ejphar.2014.03.054
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发表时间：
2014-07-05
影响因子：
5
通讯作者：
Li, Qingshan
中科院分区：
文献类型：
--
作者：
Li, Jiankuan;Ge, Rui;Li, Qingshan
内皮紧密连接是控制血管内皮细胞旁通透性的重要细胞内连接结构。氧化应激介导的内皮通透性升高与几种心血管疾病的发病机制有关。本研究在过氧化氢诱导的人内皮源性EA.hy926细胞中，研究了法瑞罗对occludin（一种与内皮紧密连接相关的跨膜蛋白）的调节作用。Western blot分析显示，H2O2暴露导致occludin表达显著降低，但对ZO-1表达影响不大，法瑞罗能显著减弱occludin表达的降低，且呈剂量依赖性。同时，免疫荧光染色也显示，法瑞罗预处理可恢复H2O2暴露引起的occludin表达缺失。进一步的研究表明，法瑞罗以剂量依赖的方式阻止h2o2诱导的细胞外信号调节激酶（ERK） 1/2的激活。使用MEK1/2特异性抑制剂U0126，证实h2o2诱导的EA.hy926细胞occludin的降低可能与ERK1/2的激活有关，提示法瑞罗对h2o2诱导的EA.hy926细胞occludin表达的调节可能与ERK1/2激活的调节有关。总之，本研究首次证明了法瑞罗对氧化应激诱导的内皮紧密连接破坏具有潜在影响，并提示法瑞罗是干预内皮通透性相关心血管疾病的潜在候选药物。(C) 2014 Elsevier B.V.版权所有
Endothelial tight junction is a crucial intracellular junctional structure that controls paracellular permeability across vascular endothelium. Oxidative stress-mediated elevation in endothelial permeability is associated with pathogenesis of several cardiovascular diseases. In the present research, the regulation of farrerol on occludin, a transmembrane proteins associated with endothelial tight junction, was investigated in hydrogen peroxide-induced human endothelium-derived EA.hy926 cells. Western blot analysis demonstrated that H2O2 exposure caused a significant decrease in occludin expression, but had little effect on ZO-1 expression, and the decrease of occludin expression was significantly attenuated by farrerol in a dose-dependent manner. Meanwhile, immunofluorescent staining assay also demonstrated that the loss of occludin expression induced by H2O2 exposure was restored by farrerol pretreatment. further investigations showed that farrerol prevented H2O2-induced activation of extracellular signal-regulated kinase (ERK) 1/2 in a dose-dependent manner. The use of U0126, a specific inhibitor of MEK1/2, proved that H2O2-inducecl decrease of occludin in EA.hy926 cells was likely associated with activation of ERK1/2, which indicated that the regulation of farrerol on occludin expression in H2O2-induced EA.hy926 cells was likely related to the modulation of ERK1/2 activation. In conclusion, the present study demonstrates for the first time that farrerol has potential effects on oxidative stress-induced endothelial tight junction disruption and suggests that farrerol is a potential candidate for the intervention of endothelial permeability-associated cardiovascular diseases. (C) 2014 Elsevier B.V. All rights reserved.