Estrogen receptor and PI3K/Akt signaling pathway involvement in S-(-)equol-induced activation of Nrf2/ARE in endothelial cells.
Estrogen receptor and PI3K/Akt signaling pathway involvement in S-(-)equol-induced activation of Nrf2/ARE in endothelial cells.
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雌激素受体和 PI3K/Akt 信号通路参与 S-(-) 雌马酚诱导的内皮细胞 Nrf2/ARE 激活
DOI：
10.1371/journal.pone.0079075
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Mi M
中科院分区：
文献类型：
--
作者：
Zhang T;Liang X;Shi L;Wang L;Chen J;Kang C;Zhu J;Mi M
S-（-）雌马酚是大豆黄酮的天然产物，据报道对心血管系统具有细胞保护作用，但其作用机制尚不清楚。有趣的是，S-（-）雌马酚是由人类肠道产生的，这表明它在生理过程中发挥作用。我们报道了用S-（-）雌马酚处理人脐静脉内皮细胞和EA.hy926细胞诱导ARE-荧光素酶报告基因活性，该活性具有剂量和时间依赖性。S-（-）雌马酚（10-250 nM）增加核因子-红细胞2相关因子2（Nrf 2）以及Nrf 2靶基因血红素加氧酶-1（HO-1）和NAD（P）H（烟酰胺腺嘌呤二核苷酸磷酸）醌氧化还原酶1（NQO 1）的基因产物。用HA-Nrf 2表达质粒转染的内皮细胞对S-（-）雌马酚暴露的反应是HA-Nrf 2、HO-1和NQO 1升高。S-（-）雌马酚处理仅轻微影响Nrf 2 mRNA，但显著增加HO-1和NQO 1 mRNA。用特异性ER抑制剂或PI 3 K/Akt（ICI 182、780和LY 294002）预处理细胞增加Nrf 2、HO-1和NQO 1蛋白，损害HA-Nrf 2的核转位，并降低ARE-荧光素酶活性。用大豆黄酮进行了相同的实验，大豆黄酮具有与S-（-）雌马酚相似的作用。此外，DPN处理（ERβ激动剂）诱导ARE-荧光素酶报告基因，促进Nrf 2核转位。用ERβ拮抗剂（PHTPP）预处理细胞可削弱S-（-）雌马酚诱导的Nrf 2激活。细胞预孵育后与S-（-）雌马酚共处理显着提高细胞存活率响应H2 O2或tBHP和减少凋亡和TUNEL阳性染色的细胞。值得注意的是，S-（-）雌马酚防止H2 O2诱导的细胞凋亡的能力在用针对Nrf 2的siRNA转染的细胞中减弱。因此，S-（-）雌马酚在细胞保护性抗氧化基因激活方面的有益作用可能代表了预防和治疗心血管疾病的新策略。
S-(-)equol, a natural product of the isoflavone daidzein, has been reported to offer cytoprotective effects with respect to the cardiovascular system, but how this occurs is unclear. Interestingly, S-(-)equol is produced by the human gut, suggesting a role in physiological processes. We report that treatment of human umbilical vein endothelial cells and EA.hy926 cells with S-(-)equol induces ARE-luciferase reporter gene activity that is dose and time dependent. S-(-)equol (10–250 nM) increases nuclear factor-erythroid 2-related factor 2 (Nrf2) as well as gene products of Nrf2 target genes heme oxygenase-1 (HO-1) and NAD(P)H (nicotinamide-adenine-dinucleotide-phosphate) quinone oxidoreductase 1 (NQO1). Endothelial cells transfected with an HA-Nrf2 expression plasmid had elevated HA-Nrf2, HO-1, and NQO1 in response to S-(-)equol exposure. S-(-)equol treatment affected Nrf2 mRNA only slightly but significantly increased HO-1 and NQO1 mRNA. The pretreatment of cells with specific ER inhibitors or PI3K/Akt (ICI182,780 and LY294002) increased Nrf2, HO-1, and NQO1 protein, impaired nuclear translocation of HA-Nrf2, and decreased ARE-luciferase activity. Identical experiments were conducted with daidzein, which had effects similar to S-(-)equol. In addition, DPN treatment (an ERβ agonist) induced the ARE-luciferase reporter gene, promoting Nrf2 nuclear translocation. Cell pretreatment with an ERβ antagonist (PHTPP) impaired S-(-)equol-induced Nrf2 activation. Pre-incubation of cells followed by co-treatment with S-(-)equol significantly improved cell survival in response to H2O2 or tBHP and reduced apoptotic and TUNEL-positively-stained cells. Notably, the ability of S-(-)equol to protect against H2O2-induced cell apoptosis was attenuated in cells transfected with an siRNA against Nrf2. Thus, beneficial effects of S-(-)equol with respect to cytoprotective antioxidant gene activation may represent a novel strategy to prevent and treat cardiovascular diseases.
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DOI：
10.1016/j.bbrc.2008.08.027
发表时间：
2008-10-24
影响因子：
3.1
作者：
Chung, Jae-Eun;Kim, Sue Yeon;Kim, Mee-Ran
通讯作者：
Kim, Mee-Ran
影响因子：
7.4
作者：
Hwang, J;Sevanian, A;Ursini, F
通讯作者：
Ursini, F
影响因子：
5.6
作者：
Froyen, Erik B.;Steinberg, Francene M.
通讯作者：
Steinberg, Francene M.
影响因子：
4.2
作者：
Cheng, Charlie;Wang, Xinwen;Chen, Changyi
通讯作者：
Chen, Changyi
影响因子：
4.2
作者：
Clerici, Carlo;Setchell, Kenneth D. R.;Morelli, Antonio
通讯作者：
Morelli, Antonio