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Pharmacologic effects of 2-methoxyestradiol on angiotensin type 1 receptor down-regulation in rat liver epithelial and aortic smooth muscle cells.

ABSTRACT: BACKGROUND:Delayed onset of cardiovascular disease (CVD) in female patients is not well understood, but could be due in part to the protective effect of estrogen before menopause. Experimental studies have identified the angiotensin type 1 receptor (AT1R) as a key factor in the progression of CVD. OBJECTIVE:We examined the effects of the estrogen metabolite 2-methoxyestradiol (2ME2) on AT1R expression. METHODS:Rat liver cells were exposed to 2ME2 for 24 hours, and angiotensin II (AngII) binding and AT1R mRNA expressions were assessed. RESULTS:In the presence of 2ME2, cells exhibited significant down-regulation of AngII binding that was both dose and time dependent, independent of estrogen receptors (ER?/ER?). Down-regulation of AngII binding was AT1R specific, with no change in receptor affinity. Under similar conditions, we observed lower expression of AT1R mRNA, significant inhibition of AngII-mediated increase in intracellular Ca(2+), and increased phosphorylation of ERK1/2. Pretreatment of cells with the MEK inhibitor PD98059 prevented 2ME2-induced ERK1/2 phosphorylation and down-regulation of AT1R expression, which suggests that the observed inhibitory effect is mediated through ERK1/2 signaling intermediates. Similar analyses in stably transfected CHO (Chinese hamster ovary) cell lines with a constitutively active cytomegalovirus promoter showed no change in AT1R expression, which suggests that 2ME2-mediated effects are through transcriptional regulation. The effects of 2ME2 on AT1R down-regulation through ERK1/2 were consistently reproduced in primary rat aortic smooth muscle cells. CONCLUSIONS:Because AT1R has a critical role in the control of CVD, 2ME2-induced changes in receptor expression may provide beneficial effects to the cardiovascular and other systems.

SUBMITTER: Koganti S

PROVIDER: S-EPMC3322289 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Pharmacologic effects of 2-methoxyestradiol on angiotensin type 1 receptor down-regulation in rat liver epithelial and aortic smooth muscle cells.

Koganti Sivaramakrishna S Snyder Russell R Thekkumkara Thomas T

Gender medicine 20120225 2

<h4>Background</h4>Delayed onset of cardiovascular disease (CVD) in female patients is not well understood, but could be due in part to the protective effect of estrogen before menopause. Experimental studies have identified the angiotensin type 1 receptor (AT1R) as a key factor in the progression of CVD.<h4>Objective</h4>We examined the effects of the estrogen metabolite 2-methoxyestradiol (2ME2) on AT1R expression.<h4>Methods</h4>Rat liver cells were exposed to 2ME2 for 24 hours, and angiotens ...[more]

PMID: 22366193

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Project description:BackgroundAngiotensin II (Ang II) signaling, including matrix metalloproteinase type II (MMP2) activation, has been linked to an age-associated increase in migration capacity of vascular smooth muscle cells (VSMC), and to other proinflammatory features of arterial aging. Calpain-1 activation is required for MMP2 expression in fibroblasts and is induced in cardiomyocytes by Ang II. The consequences of engagement of calpain-1 with its substrates, however, in governing the age-associated proinflammatory status within the arterial wall, remains unknown.Methodology/principal findingsThe present findings demonstrate that transcription, translation, and activity of calpain-1 are significantly up-regulated in rat aortae or early-passage aortic VSMC from old (30-mo) rats compared to young (8-mo). Dual immunolabeling of the arterial wall indicates that colocalization of calpain-1 and Ang II increases within the aged arterial wall. To further explore the relationship of calpain-1 to Ang II, we chronically infused Ang II into young rats, and treated cultured aortic rings or VSMC with Ang II. We also constructed adenoviruses harboring calpain-1 (CANP1) or its endogenous inhibitor calpastatin (CAST) and infected these into VSMC. Ang II induces calpain-1 expression in the aortic walls in vivo and ex vivo and VSMC in vitro. The Ang II mediated, age-associated increased MMP2 activity and migration in VSMC are both blocked by calpain inhibitor 1 or CAST. Over-expression of calpain-1 in young VSMC results in cleavage of intact vimentin, and an increased migratory capacity mimicking that of old VSMC, which is blocked by the MMP inhibitor, GM6001.Conclusions/significanceCalpain-1 activation is a pivotal molecular event in the age-associated arterial Ang II/MMP2 signaling cascade that is linked to cytoskeleton protein restructuring, and VSMC migration. Therefore, targeting calpain-1 has the potential to delay or reverse the arterial remodeling that underlies age-associated diseases i.e. atherosclerosis.

Dataset Information

Pharmacologic effects of 2-methoxyestradiol on angiotensin type 1 receptor down-regulation in rat liver epithelial and aortic smooth muscle cells.

Publications

Pharmacologic effects of 2-methoxyestradiol on angiotensin type 1 receptor down-regulation in rat liver epithelial and aortic smooth muscle cells.

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