2-Methoxyestradiol, a novel pharmacological inhibitor for Angiotensin Type I Receptor
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Delayed onset of cardiovascular(CVD) disease among females is not well understood, but could be in part due to the protective effect of estrogen before menopause. Experimental studies have identified the angiotensin type I receptor (AT1R) as a key factor in the progression of CVD.In this study, we have examined the effects and mechanism of the estrogen metabolite, 2-Methoxyestradiol (2ME2), on AT1R expression.The study used rat liver epithelial cells as the primary cell model to determine the 2ME2 induced cellular signaling, the overall concept was further confirmed in rat aortic smooth muscle cells and further validated in vivo in an animal model of hypertension. When rat liver epithelial cells were exposed to 2ME2 for 24 hours, cells exhibited significant down-regulation of AngII binding and AT1R mRNA, independent of estrogen receptors (ERα/ERβ) with no change in receptor affnity.Significant inhibition of AngII mediated increase in intracellular Ca+2 and increased phopsphorylation of ERK1/2 were also observed.Similar analyses in stably transfected CHO cell lines with a constitutively active cytomegalovirus (CMV) promoter showed no change in AT1R expression suggesting the transcriptional regulation.2ME2 has been shown to bind specifically to endoplasmic reticulum bound G-protein coupled receptor 30(GPR30), activating matrix metalloprpteinases (MMPs) to induce epidermal growth factor receptor (EGFR) activation ultimately leading to AT1R down-regulation.2ME2 treatment showed significant down-regulation of systolic, diastolic and mean arterial blood pressure, as well as a decrease in body weight in spontaneously hypertensive rats (SHR).Consistent with the reduction in blood pressure, we observed AT1R protein and mRNA expression down-regulation in the renal cortical tissue. In summary, as AT1R plays a critical role in the control of cardiovascular diseases, 2ME2 induced changes in receptor expression may provide beneficial effects to the cardiovascular, as well as other systems.