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-Estradiol inhibits cyclic strain-induced endothelin-1 gene expression within vascular endothelial cells
1 Department of Medicine, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan; Department of Medicine and Clinical Research Center, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan
2 Department of Internal Medicine, National University Hosptial and National Taiwan University College of Medicine, Taipei, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
3 Department of Medicine and Clinical Research Center, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan
4 Department of Medicine, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan
5 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
6 Department of Cardiovascular Surgery, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
7 Department of Medicine, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan; Department of Internal Medicine, National University Hosptial and National Taiwan University College of Medicine, Taipei, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
* To whom correspondence should be addressed. E-mail: thcheng{at}gate.sinica.edu.tw.
It has been well documented previously that 17
-estradiol (E2) exerts a protective effect
upon cardiovascular tissue. The possible role of E2 in the regulation of endothelin-1 (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 17
-estradiol, inhibited the level of strain-induced ET-1 gene expression and also the 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 µM). E2 also inhibited the strain-enhanced NADPH oxidase activity, intracellular reactive oxygen species (ROS) generation as measured by a 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 demonstrate
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 upon the cardiovascular system.
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