This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Barchiesi, F. Articles by Dubey, R. K. Search for Related Content PubMed PubMed Citation Articles by Barchiesi, F. Articles by Dubey, R. K. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB ESTRADIOL

Differential Regulation of Estrogen Receptor Subtypes and ß in Human Aortic Smooth Muscle Cells by Oligonucleotides and Estradiol

Department of Obstetrics and Gynecology (F.B., B.I., R.K.D.), Clinic for Endocrinology, University Hospital Zurich, 8091 Zurich, Switzerland; Center for Clinical Pharmacology (E.K.J., D.G.G., R.K.D.), Departments of Medicine and Pharmacology (E.K.J.), University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213-2582; and Preclinical Pharma Research 68/209 (J.F.), F. Hoffmann La-Roche, CH-4070 Basel, Switzerland

Address all correspondence and requests for reprints to: Dr. Raghvendra K. Dubey, Department of Obstetrics and Gynecology, Clinic for Endocrinology D217, NORD-1 Frauenklinik University Hospital Zurich, CH-8091 Zurich, Switzerland. E-mail: raghvendra.dubey{at}usz.ch.

We investigated the mechanisms regulating estrogen receptor (ER) expression in human aortic smooth muscle cells (HASMCs) and the mechanisms by which estradiol inhibits HASMC growth. The autologous down-regulation pathway involves binding of liganded ER to the ER gene, thus suppressing transcription. Blockade of this pathway with sense and AS-OLIGOs to ERs up-regulated the expression of ER but not ERß. Activation of the autologous down-regulation pathway with ER agonists down-regulated the expression of ER but not ERß. The proteasomal degradation pathway entails ubiquination of liganded ER, followed by proteasome-mediated degradation. Blockade of the proteasomal degradation pathway increased the expression of ERß. Up-regulation of ER by AS-OLIGOs did not increase the antimitogenic effects of estradiol on HASMCs; the estradiol metabolites 2-hydroxyestradiol and 2-methoxyestradiol were more potent inhibitors of HASMC growth, compared with estradiol; and blockade of metabolism of estradiol to hydroxyestradiols and methoxyestradiols abrogated the inhibitory effects of estradiol on HASMC growth. We conclude that, in HASMCs: 1) the expression of ER is regulated by the autologous downregulation pathway; 2) the expression of ERß is governed by the proteasomal degradation pathway; and 3) the antigrowth effects of estradiol are not mediated by ER, but rather by metabolism of estradiol to methoxyestradiols.

This work was supported by Swiss National Science Foundation Grant 32-64040.00.

Abbreviations: AS, Antisense (OLIGO); COMT, catechol-O-methyltransferase; DPN, 2,3-bis(4-hydroxyphenyl)propionitrile; ER, estrogen receptor; HASMC, human aortic smooth muscle cell; MEK, MAPK kinase; MPP, 4,4'-[4-methyl-5-[4-[2-(1-piperidnyl) ethoxy]-phenyl-1H-pyrazole]-1,3 diyl]-bis-phenol HCl; OLIGO, oligonucleotide; PPT, propyl pyrazole triol; S, sense (OLIGO); Scr, scrambled (OLIGO); SDS, sodium dodecyl sulfate; SMC, smooth muscle cell.

This article has been cited by other articles:

				R. K. Dubey, B. Imthurn, and E. K. Jackson 2-Methoxyestradiol: A Potential Treatment for Multiple Proliferative Disorders Endocrinology, September 1, 2007; 148(9): 4125 - 4127. [Full Text] [PDF]

				C. Pinna, C. Bolego, P. Sanvito, V. Pelosi, R. Baetta, A. Corsini, R. M. Gaion, and A. Cignarella Raloxifene Elicits Combined Rapid Vasorelaxation and Long-Term Anti-Inflammatory Actions in Rat Aorta J. Pharmacol. Exp. Ther., December 1, 2006; 319(3): 1444 - 1451. [Abstract] [Full Text] [PDF]

				C. Bolego, E. Vegeto, C. Pinna, A. Maggi, and A. Cignarella Selective Agonists of Estrogen Receptor Isoforms: New Perspectives for Cardiovascular Disease Arterioscler. Thromb. Vasc. Biol., October 1, 2006; 26(10): 2192 - 2199. [Abstract] [Full Text] [PDF]

				D. Titolo, F. Cai, and D. D. Belsham Coordinate Regulation of Neuropeptide Y and Agouti-Related Peptide Gene Expression by Estrogen Depends on the Ratio of Estrogen Receptor (ER) {alpha} to ER{beta} in Clonal Hypothalamic Neurons Mol. Endocrinol., September 1, 2006; 20(9): 2080 - 2092. [Abstract] [Full Text] [PDF]

				F. Barchiesi, E. K. Jackson, J. Fingerle, D. G. Gillespie, B. Odermatt, and R. K. Dubey 2-Methoxyestradiol, an Estradiol Metabolite, Inhibits Neointima Formation and Smooth Muscle Cell Growth via Double Blockade of the Cell Cycle Circ. Res., August 4, 2006; 99(3): 266 - 274. [Abstract] [Full Text] [PDF]

				M. R. Meyer, E. Haas, and M. Barton Gender Differences of Cardiovascular Disease: New Perspectives for Estrogen Receptor Signaling Hypertension, June 1, 2006; 47(6): 1019 - 1026. [Full Text] [PDF]

				E Horner-Glister, M Maleki-Dizaji, C J Guerin, S M Johnson, J Styles, and I N H White Influence of oestradiol and tamoxifen on oestrogen receptors-{alpha} and -{beta} protein degradation and non-genomic signalling pathways in uterine and breast carcinoma cells J. Mol. Endocrinol., December 1, 2005; 35(3): 421 - 432. [Abstract] [Full Text] [PDF]

				K. F. Koehler, L. A. Helguero, L.-A. Haldosen, M. Warner, and J.-A. Gustafsson Reflections on the Discovery and Significance of Estrogen Receptor {beta} Endocr. Rev., May 1, 2005; 26(3): 465 - 478. [Abstract] [Full Text] [PDF]

				R. K. Dubey, E. K. Jackson, D. G. Gillespie, M. Rosselli, F. Barchiesi, A. Krust, H. Keller, L. C. Zacharia, and B. Imthurn Cytochromes 1A1/1B1- and Catechol-O-Methyltransferase-Derived Metabolites Mediate Estradiol-Induced Antimitogenesis in Human Cardiac Fibroblast J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 247 - 255. [Abstract] [Full Text] [PDF]