Abstract

It has been well documented previously that 17β-estradiol (E 2) exerts a protective effect on cardiovascular tissue. The possible role of E 2 in the regulation of endothelin (ET)-1 production has been previously reported, although the complex mechanisms by which E 2 inhibits ET-1 expression are not completely understood. The aims of this study were to examine whether E 2 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, E 2 (1-100 nM), but not 17α-estradiol, inhibited the level of strain-induced ET-1 gene expression and also peptide secretion. This inhibitory effect elicited by E 2 was able to be prevented by the coincubation of endothelial cells with the estrogen receptor antagonist ICI-182,780 (1 μM). E 2 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 E 2 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 E 2 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.

Original languageEnglish
Pages (from-to)H1254-H1261
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume287
Issue number3 56-3
DOIs
Publication statusPublished - Sep 2004

Keywords

  • Extracellular signal-regulated kinase
  • Reactive oxygen species
  • Strain

ASJC Scopus subject areas

  • Physiology

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