Document Detail

Both estrogen and raloxifene cause G1 arrest of vascular smooth muscle cells.
MedLine Citation:
PMID:  12904179     Owner:  NLM     Status:  MEDLINE    
The proliferation of vascular smooth muscle cells (VSMC) is a crucial pathophysiological process in the development of atherosclerosis. Although estrogen is known to inhibit the proliferation of VSMC, the mechanism responsible for this effect remains to be elucidated. In addition, the effect of raloxifene on VSMC remains unknown. We have shown here that 17beta-estradiol (E(2)) and raloxifene significantly inhibited the platelet-derived growth factor (PDGF)-stimulated proliferation of cultured human VSMC. Flow cytometry demonstrated that PDGF-stimulated S-phase progression of the cell cycle in VSMC was also suppressed by E(2) or raloxifene. We found that PDGF-induced phosphorylation of retinoblastoma protein (pRb), whose hyperphosphorylation is a hallmark of the G1-S transition in the cell cycle, was significantly inhibited by E(2) and raloxifene. These effects were associated with a decrease in cyclin D1 expression, without a change in cyclin-dependent kinase 4 or cyclin-dependent kinase inhibitor, p27(kip1) expression. ICI 182,780 abolished the inhibitory effects of E(2) and raloxifene on PDGF-induced pRb phosphorylation. Next, we examined which estrogen receptor (ER) is necessary for these effects of E(2) and raloxifene. Since VSMC express both ERalpha and ERbeta, A10, a rat aortic smooth muscle cell line that expresses ERbeta but not ERalpha, was used. The dose-dependent stimulation of A10 cell proliferation by PDGF was not inhibited by E(2) or raloxifene in contrast to the results obtained in VSMC. Moreover, E(2) and raloxifene significantly inhibited the PDGF-induced cyclin D1 promoter activity in A10 cells transfected with cDNA for ERalpha but not in the parental cells. These results suggested that E(2) and raloxifene exert an antiproliferative effect in VSMC treated with PDGF, at least in part through inhibition of pRb phosphorylation, and that the inhibitory effects of E(2) and raloxifene may be mainly mediated by ERalpha.
K Takahashi; M Ohmichi; M Yoshida; K Hisamoto; S Mabuchi; E Arimoto-Ishida; A Mori; S Tsutsumi; K Tasaka; Y Murata; H Kurachi
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  The Journal of endocrinology     Volume:  178     ISSN:  0022-0795     ISO Abbreviation:  J. Endocrinol.     Publication Date:  2003 Aug 
Date Detail:
Created Date:  2003-08-07     Completed Date:  2003-10-07     Revised Date:  2013-06-11    
Medline Journal Info:
Nlm Unique ID:  0375363     Medline TA:  J Endocrinol     Country:  England    
Other Details:
Languages:  eng     Pagination:  319-29     Citation Subset:  IM    
Department of Obstetrics and Gynecology, Yamagata University School of Medicine, 2-2-2 Iidanishi, Yamagata, Yamagata 990-9585, Japan.
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MeSH Terms
Blotting, Western / methods
Cell Division / drug effects
Cell Line
Cells, Cultured
Cyclin D1 / metabolism
Depression, Chemical
Estradiol / analogs & derivatives*,  pharmacology*
Estrogen Receptor alpha
Flow Cytometry
G1 Phase*
Muscle, Smooth, Vascular / cytology*,  drug effects,  metabolism
Phosphorylation / drug effects
Platelet-Derived Growth Factor / pharmacology
Raloxifene / pharmacology*
Receptors, Estrogen / genetics,  metabolism
Retinoblastoma Protein / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Selective Estrogen Receptor Modulators / pharmacology*
Transfection / methods
Reg. No./Substance:
0/Estrogen Receptor alpha; 0/Platelet-Derived Growth Factor; 0/Receptors, Estrogen; 0/Retinoblastoma Protein; 0/Selective Estrogen Receptor Modulators; 136601-57-5/Cyclin D1; 22X328QOC4/fulvestrant; 50-28-2/Estradiol; 84449-90-1/Raloxifene

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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