Estrogen receptor α mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen
Estrogen receptor α mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen
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DOI：
10.1172/jci5347
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发表时间：
1999-02-01
影响因子：
15.9
通讯作者：
Shaul, PW
中科院分区：
文献类型：
--
作者：
Chen, Z;Yuhanna, IS;Shaul, PW
雌激素是一种重要的血管保护分子，通过激活内皮型一氧化氮合酶（eNOS）引起血管快速扩张，其机制尚不清楚。在完整的绵羊内皮细胞的研究中，17 β-雌二醇（E-2）引起急性（5分钟）激活eNOS，不受放线菌素D的影响，但完全抑制伴随的急性治疗与特定的雌激素受体（ER）拮抗剂。已知转录因子ER α的过表达导致对E-2的急性反应的显著增强，并且这被ER拮抗剂阻断，对E-2是特异性的，并且需要ER α结合结构域。此外，eNOS对E-2的急性反应在用野生型ER α和eNOS共转染的COS-7细胞中重建，但不通过单独转染eNOS。此外，酪氨酸激酶或丝裂原活化蛋白（MAP）激酶激酶的抑制阻止eNOS的激活由E-2，和E-2引起的快速ER依赖性激活MAP激酶。这些研究结果表明，雌激素对心血管生理学的短期作用是由ER α介导的，ER α以一种新的非基因组方式通过MAP激酶依赖性机制激活eNOS。
Estrogen is an important vasoprotective molecule that causes the rapid dilation of blood vessels by activating endothelial nitric oxide synthase (eNOS) through an unknown mechanism. In studies of intact ovine endothelial cells, 17 beta-estradiol (E-2) caused acute (five-minute) activation of eNOS that was unaffected by actinomycin D but was fully inhibited by concomitant acute treatment with specific estrogen receptor (ER) antagonists. Overexpression of the known transcription factor ER alpha led to marked enhancement of the acute response to E-2, and this was blocked by ER antagonists, was specific to E-2, and required the ER alpha hormone-binding domain. In addition, the acute response of eNOS to E-2 was reconstituted in COS-7 cells cotransfected with wild-type ER alpha and eNOS, but not by transfection with eNOS alone. Furthermore, the inhibition of tyrosine kinases or mitogen-activated protein (MAP) kinase kinase prevented the activation of eNOS by E-2, and E-2 caused rapid ER-dependent activation of MAP kinase. These findings demonstrate that the short-term effects of estrogen central to cardiovascular physiology are mediated by ER alpha functioning in a novel, nongenomic manner to activate eNOS via MAP kinase-dependent mechanisms.