2-Methoxyestradiol, a novel pharmacological inhibitor for Angiotensin Type I Receptor

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Title: 2-Methoxyestradiol, a novel pharmacological inhibitor for Angiotensin Type I Receptor
Author: Koganti, Sivaramakrishna
Abstract: 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 .
URI: http : / /hdl .handle .net /2346 /45425
Date: 2012-05

Citation

2-Methoxyestradiol, a novel pharmacological inhibitor for Angiotensin Type I Receptor. Doctoral dissertation, Texas Tech University. Available electronically from http : / /hdl .handle .net /2346 /45425 .

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