Estrogen induces the Akt-dependent activation of endothelial nitric-oxide synthase in vascular endothelial cells
Estrogen induces the Akt-dependent activation of endothelial nitric-oxide synthase in vascular endothelial cells
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DOI：
10.1074/jbc.m005036200
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发表时间：
2001-02-02
影响因子：
4.8
通讯作者：
Murata, Y
中科院分区：
文献类型：
--
作者：
Hisamoto, K;Ohmichi, M;Murata, Y
尽管已知雌激素可以激活血管内皮细胞中的内皮一氧化氮合酶（eNOS），但导致这种作用的分子机制仍有待阐明。在人脐静脉内皮细胞 (HUVEC) 和猿猴病毒 40 转化的大鼠肺血管内皮细胞 (TRLEC) 的研究中，17β-雌二醇 (E2)（而非 17α-E2）引起 eNOS 的急性激活，这种激活不受放线菌素 D 的影响，并被纯雌激素受体拮抗剂 ICI-182,780 特异性阻断，用 17β-E2 处理 TRLEC 和 HUVEC 都会刺激 Akt 的激活，PI3K 抑制剂渥曼青霉素阻断 17β-E2 诱导的 Akt 激活，17β-E2 诱导的 Akt 激活也被 ICI-182,780 抑制，但不被放线菌素 D 抑制。 17β-E2 诱导的 eNOS 激活。此外，17β-E2诱导的Akt激活实际上增强了eNOS的磷酸化，17β-E2诱导的Akt激活依赖于细胞外和细胞内Ca2+。我们进一步检查了瞬时转染雌激素受体cw (ER α)或雌激素受体β (ER β)的cDNA的中国仓鼠卵巢(CHO)细胞中17β-E2诱导的Akt活性，17β-E2刺激表达ERa的CHO细胞中的Akt活化，但不刺激表达ERP的CHO细胞中的Akt活化。我们的研究结果表明17P-E2通过Akt依赖性机制诱导eNOS活化，这是由 ER α 通过非基因组机制介导的。
Although estrogen is known to activate endothelial nitric oxide synthase (eNOS) in the vascular endothelium, the molecular mechanism responsible for this effect remains to be elucidated. In studies of both human umbilical vein endothelial cells (HUVECs) and simian virus 40-transformed rat lung vascular endothelial cells (TRLECs), 17 beta -estradiol (E2), but not 17 alpha -E2, caused acute activation of eNOS that was unaffected by actino-mycin D and was specifically blocked by the pure estrogen receptor antagonist ICI-182,780, Treatment of both TRLECs and HUVECs with 17 beta -E2 stimulated the activation of Akt, and the PI3K inhibitor wortmannin blocked the 17 beta -E2-induced activation of Akt, 17 beta -E2-induced Akt activation was also inhibited by ICI-182,780, but not by actinomycin D, Either treatment with wortmannin or exogenous expression of a dominant negative Akt in TRLECs decreased the 17 beta -E2-induced eNOS activation. Moreover, 17 beta -E2-induced Akt activation actually enhances the phosphorylation of eNOS, 17 beta -E2-induced Akt activation was dependent on both extracellular and intracellular Ca2+. We further examined the 17 beta -E2-induced Akt activity in Chinese hamster ovary (CHO) cells transiently transfected with cDNAs for estrogen receptor cw (ER alpha) or estrogen receptor beta (ER beta), 17 beta -E2 stimulated the activation of Akt in CHO cells expressing ERa but not in CHO cells expressing ERP, Our findings suggest that 17P-E2 induced eNOS activation through an Akt-dependent mechanism, which is mediated by ER alpha via a nongenomic mechanism.