17β-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.

Sex differences in endothelin-1-mediated vasoconstrictor tone in middle-aged and older adults

“…Estrogen suppresses ET-1 expression in a number of models, including humans (17,19,29,43,44). In addition, estrogen treatment of coronary artery rings reduces ET-1-mediated vasoconstriction (38).…”

Estrogen is a modulator of vascular inflammation

“…ET-1 acts by binding through its receptors, termed ET A and ET B receptors, which mediates cellular effects through activation of protein kinase C (PKC) and other proinflammatory signaling kinases. Increased ET-1 activity is associated with vascular diseases with inflammatory etiology such as hypertension and atherosclerosis (reviewed in (25). In addition, estrogen metabolites such as 2-hydroxyestradiol (2-HE) and 2-methoxyestradiol (2-ME) inhibit ET-1 synthesis through ER-independent pathways (26).…”

Luteolin Inhibits Endothelin-1 Secretion in Cultured Endothelial Cells

“…7,8) In the present study, a decrease in ET-1 gene expression by luteolin might occur via estrogen receptors binding nonglycoside luteolin in the intracellular mechanism. From these results, we conclude that luteolin can potently inhibit the secretion and gene expression of ET-1 in porcine aortic endothelial cells.…”