title: 17beta-estradiol inhibits cyclic strain-induced endothelin-1 gene expression within vascular endothelial cells.
abstract: It has been well documented previously that 17beta-estradiol (E2) exerts a protective effect on cardiovascular tissue. The possible role of E2 in the regulation of endothelin (ET)-1 production has been previously reported, although the complex mechanisms by which E2 inhibits ET-1 expression are not completely understood. The aims of this study were to examine whether E2 was able to alter strain-induced ET-1 gene expression and also to identify the putative underlying signaling pathways that exist within endothelial cells. For cultured endothelial cells, E2 (1-100 nM), but not 17alpha-estradiol, inhibited the level of strain-induced ET-1 gene expression and also peptide secretion. This inhibitory effect elicited by E2 was able to be prevented by the coincubation of endothelial cells with the estrogen receptor antagonist ICI-182,780 (1 microM). E2 also inhibited strain-enhanced NADPH oxidase activity and intracellular reactive oxygen species (ROS) generation as measured by the redox-sensitive fluorescent dye 2',7'-dichlorofluorescin diacetate and the level of extracellular signal-regulated kinase (ERK) phosphorylation. Furthermore, the presence of E2 and antioxidants such as N-acetylcysteine and diphenylene iodonium were able to elicit a decrease in the level of strain-induced ET-1 secretion, ET-1 promoter activity, ET-1 mRNA, ERK phosphorylation, and activator protein-1 binding activity. In summary, we demonstrated, for the first time, that E2 inhibits strain-induced ET-1 gene expression, partially by interfering with the ERK pathway via the attenuation of strain-induced ROS generation. Thus this study delivers important new insight regarding the molecular pathways that may contribute to the proposed beneficial effects of estrogen on the cardiovascular system.
authors.affiliation: Graduate Institute of Medical Sciences and Department of Physiology, School of Medicine, Taipei Medical University, Republic of China.
authors.forename: Shu-Hui
authors.initials: SH
authors.lastname: Juan
authors.forename: Jin-Jer
authors.initials: JJ
authors.lastname: Chen
authors.forename: Cheng-Hsien
authors.initials: CH
authors.lastname: Chen
authors.forename: Heng
authors.initials: H
authors.lastname: Lin
authors.forename: Ching-Feng
authors.initials: CF
authors.lastname: Cheng
authors.forename: Ju-Chi
authors.initials: JC
authors.lastname: Liu
authors.forename: Ming-Hsiung
authors.initials: MH
authors.lastname: Hsieh
authors.forename: Yen-Ling
authors.initials: YL
authors.lastname: Chen
authors.forename: Hung-Hsing
authors.initials: HH
authors.lastname: Chao
authors.forename: Tso-Hsiao
authors.initials: TH
authors.lastname: Chen
authors.forename: Paul
authors.initials: P
authors.lastname: Chan
authors.forename: Tzu-Hurng
authors.initials: TH
authors.lastname: Cheng
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D009861:Onium Compounds / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013314:Stress, Mechanical; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors
chemical_list: D000975:Antioxidants; D019332:Endothelin-1; D009861:Onium Compounds; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D004958:Estradiol; C007517:diphenyleneiodonium; D019255:NADPH Oxidases; D020928:Mitogen-Activated Protein Kinases; D000111:Acetylcysteine