title: The isoflavone metabolite cis-tetrahydrodaidzein inhibits ERK-1 activation and proliferation in human vascular smooth muscle cells.
abstract: Phytoestrogens have recently been proposed as alternatives to estrogens for cardiovascular protection; however, the effect of their metabolites on vascular biology is unclear. We studied the effect of a red clover-derived isoflavone metabolite cis-tetrahydrodaidzein (cis-THD) on human vascular smooth muscle cell (VSMC) proliferation. Cis-THD significantly inhibited platelet-derived growth factor (PDGF) BB-induced DNA synthesis (10% at 1 nmol/L, 17% at 10, 100 nmol/L; 17beta-estradiol: 27% inhibition at 1, 10 nmol/L, 33% at 100 nmol/L). Cis-THD reduced PDGF BB-induced increase in cell numbers. Cis-THD showed high binding affinity to estrogen receptors (ER) by ER competitor assays; its inhibitory effect on DNA synthesis was abolished by the ER antagonist ICI 182780 (100 nmol/L), indicating ER-mediation. Immunoprecipitation assays revealed that cis-THD inhibited PDGF BB-stimulated activation of mitogen-activated protein (MAP) kinase ERK-1 by 34% at 1 nmol/L, 58% at 10 nmol/L, and 81% at 100 nmol/L, while MAP kinase JNK and p38 activities were unaltered. Thus, the isoflavone metabolite cis-THD inhibits PDGF-induced ERK-1 activation and cell proliferation in human VSMC, suggesting a potential beneficial effect in cardiovascular protection.
authors.affiliation: Hormones and the Vasculature Laboratory, Baker Medical Research Institute, Melbourne, Australia.
authors.forename: Shanhong
authors.initials: S
authors.lastname: Ling
authors.forename: Aozhi
authors.initials: A
authors.lastname: Dai
authors.forename: Maro R I
authors.initials: MR
authors.lastname: Williams
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Husband
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Nestel
authors.forename: Paul A
authors.initials: PA
authors.lastname: Komesaroff
authors.forename: Krishnankutty
authors.initials: K
authors.lastname: Sudhir
mesh_terms: D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D048670:MAP Kinase Kinase 4; D008323:Mammary Arteries / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D004791:Enzyme Inhibitors; D007529:Isoflavones; D011960:Receptors, Estrogen; C433164:tetrahydrodaidzein; D048031:JNK Mitogen-Activated Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases