title: Dehydroepiandrosterone inhibits human vascular smooth muscle cell proliferation independent of ARs and ERs.
abstract: Dehyroepiandrosterone (DHEA), an adrenal-derived steroid, has been clinically implicated in protection against coronary artery disease and experimentally in inhibition of atherosclerosis and plaque progression. Because DHEA is enzymatically metabolized to androgens or estrogens, it is not clear whether DHEA exerts effects directly or after conversion to these hormones, both of which are associated with well-characterized pathways of action. We therefore examined the effects of DHEA on proliferation of human vascular smooth muscle cells (VSMCs) in culture in the presence or absence of the ER antagonist ICI 182,780 and the AR antagonist flutamide and compared them with the effects of 17beta-estradiol, androstenedione, and T. We also determined the affinity of DHEA for ERs and ARs in VSMC and its specific binding in intact cells. To explore a possible mechanism for DHEA action in these cells, we measured the phosphorylation of ERK-1, c-jun N-terminal protein kinase, and p38 (three members of the MAPK superfamily). Both DHEA and 17beta-estradiol significantly inhibited platelet derived growth factor (PDGF)-BB-induced increases in VSMC proliferation, whereas androstenedione and T increased proliferation. Although E2-induced inhibition of the PDGF effect was abolished by ICI 182,780 and T-induced stimulation was abolished by flutamide, neither receptor antagonist altered the inhibitory effect of DHEA. Binding studies confirmed the presence of both ERs and ARs; DHEA showed minimal affinity for either receptor but bound specifically and with high affinity to putative receptors in intact cells. Following 4-h incubation with DHEA (1-100 nM), ERK1 phosphorylation was significantly reduced in a dose-dependent manner, whereas neither c-jun N-terminal protein kinase nor p38 kinase activity was altered by either PDGF-BB or DHEA. DHEA inhibits human VSMC proliferation by a mechanism independent of either ARs or ERs, presumably via a DHEA-specific receptor that involves ERK1 signaling pathways.
authors.affiliation: Baker Medical Research Institute and Alfred Hospital, Melbourne, Victoria 3181, Australia.
authors.forename: Maro R I
authors.initials: MR
authors.lastname: Williams
authors.forename: Shanhong
authors.initials: S
authors.lastname: Ling
authors.forename: Tye
authors.initials: T
authors.lastname: Dawood
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Hashimura
authors.forename: Aozhi
authors.initials: A
authors.lastname: Dai
authors.forename: He
authors.initials: H
authors.lastname: Li
authors.forename: Jun-Ping
authors.initials: JP
authors.lastname: Liu
authors.forename: John W
authors.initials: JW
authors.lastname: Funder
authors.forename: Krishnankutty
authors.initials: K
authors.lastname: Sudhir
authors.forename: Paul A
authors.initials: PA
authors.lastname: Komesaroff
mesh_terms: D059002:Androgen Receptor Antagonists; D000735:Androstenedione / Q000494:pharmacology; D000077214:Becaplermin; D001665:Binding Sites; D002455:Cell Division; D002478:Cells, Cultured; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D004958:Estradiol / Q000494:pharmacology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000032:analysis; D020928:Mitogen-Activated Protein Kinases / Q000032:analysis; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011944:Receptors, Androgen / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013739:Testosterone / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D059002:Androgen Receptor Antagonists; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D000077214:Becaplermin; D013739:Testosterone; D000735:Androstenedione; D003687:Dehydroepiandrosterone; D004958:Estradiol; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases