Oestrogen and progesterone inhibit the stimulated production of endothelin-1.
Oestrogen and progesterone inhibit the stimulated production of endothelin-1.
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DOI：
10.1042/bj3301097
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发表时间：
1998-03
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影响因子：
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通讯作者：
A. K. Morey;M. Razandi;A. Pedram;R. Hu;Bruce A. Prins;E. Levin
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作者：
A. K. Morey;M. Razandi;A. Pedram;R. Hu;Bruce A. Prins;E. Levin
内皮素-1（ET-1）等重要的血管蛋白促进心血管疾病的发展。雌激素，也许还有孕激素，通过不完全了解的细胞机制来预防女性血管疾病的发展。我们推测雌二醇或孕酮可能调节ET-1的产生作为一个潜在的新机制。我们发现，血清和血管紧张素Ⅱ（AII）显着刺激培养的牛主动脉内皮细胞ET-1的分泌，抑制50-75%的雌二醇或孕酮。血清和AII刺激ET-1 mRNA水平，抑制至少70%的雌二醇和孕酮。血清主要通过ET-1启动子的前43个核苷酸刺激ET-1的转录，但雌二醇和孕酮不抑制这一点。相反，AII通过核苷酸-143至-98刺激ET-1转录，特别涉及激活蛋白-1（AP-1）-102位点。雌二醇和孕酮引起AII刺激的野生型构建体的60-70%抑制。143 ET-1/CAT活性（CAT是氯霉素酰基转移酶）。ET-1转录的AII刺激严重依赖于丝裂原活化蛋白激酶（erk）活性的刺激，雌二醇和孕酮抑制。总之，我们发现性类固醇抑制AII诱导的ERK信号传导到ET-1转录程序。雌二醇和孕酮负转录调节的这种新机制减少了ET-1的产生，可能有助于这些类固醇的血管保护作用。
Important vascular proteins such as endothelin-1 (ET-1) promote the development of cardiovascular diseases. Oestrogen, and perhaps progesterone, prevent the development of vascular disease in women through incompletely understood cellular mechanisms. We hypothesized that oestradiol or progesterone might regulate the production of ET-1 as a potential novel mechanism. We found that serum and angiotensin II (AII) significantly stimulated ET-1 secretion from cultured bovine aortic endothelial cells, inhibited 50-75% by oestradiol or by progesterone. Serum and AII stimulated ET-1 mRNA levels, inhibited at least 70% by oestradiol and by progesterone. Serum stimulated ET-1 transcription mainly through the first 43 nucleotides of the ET-1 promoter, but oestradiol and progesterone did not inhibit this. In contrast, AII stimulated ET-1 transcription through nucleotides -143 to -98, specifically involving an activator protein-1 (AP-1) site at -102. Oestradiol and progesterone caused a 60-70% inhibition of AII-stimulated wild-type construct -. 143ET-1/CAT activity (CAT is chloramphenicol acyltransferase). AII-stimulation of ET-1 transcription was critically dependent on stimulation of mitogen-activated protein kinase (erk) activity, inhibited by oestradiol and progesterone. In summary, we found that sex steroids inhibit AII-induced erk signalling to the ET-1 transcriptional programme. This novel mechanism of negative transcriptional regulation by oestradiol and progesterone decreases the production of ET-1, potentially contributing to the vascular protective effects of these steroids.