title: Differential regulation of estrogen receptor subtypes alpha and beta in human aortic smooth muscle cells by oligonucleotides and estradiol.
abstract: 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 ERalpha but not ERbeta. Activation of the autologous down-regulation pathway with ER agonists down-regulated the expression of ERalpha but not ERbeta. The proteasomal degradation pathway entails ubiquination of liganded ER, followed by proteasome-mediated degradation. Blockade of the proteasomal degradation pathway increased the expression of ERbeta. Up-regulation of ERalpha 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 ERalpha is regulated by the autologous downregulation pathway; 2) the expression of ERbeta is governed by the proteasomal degradation pathway; and 3) the antigrowth effects of estradiol are not mediated by ERalpha, but rather by metabolism of estradiol to methoxyestradiols.
authors.affiliation: Department of Obstetrics and Gynecology, Clinic for Endocrinology, University Hospital Zurich, 8091 Zurich, Switzerland.
authors.forename: Federica
authors.initials: F
authors.lastname: Barchiesi
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Jackson
authors.forename: Bruno
authors.initials: B
authors.lastname: Imthurn
authors.forename: Juergen
authors.initials: J
authors.lastname: Fingerle
authors.forename: Delbert G
authors.initials: DG
authors.lastname: Gillespie
authors.forename: Raghvendra K
authors.initials: RK
authors.lastname: Dubey
mesh_terms: D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015536:Down-Regulation; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology*; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D005260:Female; D006801:Humans; D009097:Multienzyme Complexes / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009841:Oligonucleotides / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D011960:Receptors, Estrogen / Q000378:metabolism*
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D009097:Multienzyme Complexes; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D011960:Receptors, Estrogen; D004958:Estradiol; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex