title: Estradiol regulates monocyte chemotactic protein-1 in human coronary artery smooth muscle cells: a mechanism for its antiatherogenic effect.
abstract: OBJECTIVE
  The protective effect of estrogen against early atherosclerosis in animal models is well documented, but the mechanisms responsible for this effect are not well understood. The earliest recognizable event in the pathogenesis of atherosclerosis is an increased recruitment of macrophages into the arterial subendothelium. Macrophages first play a protective role by removing low-density lipoproteins, but when the cholesterol is in excess, macrophages are converted into foam cells and form atheromas. Recent human and animal data indicate that the recruitment of macrophages to the arterial wall is mediated by monocyte chemotactic protein-1 (MCP-1). We hypothesized that one of the mechanisms of estrogen's protective effect against atherosclerosis may be the down-regulation of MCP-1 expression in the arterial wall.
  
  
  METHODS
  Human coronary artery smooth muscle cells were replicated to confluence in smooth muscle cell basal medium supplemented with growth factors and 5% fetal bovine serum. Before each experiment, cells were incubated for 24 h with phenol red-free medium containing 5% charcoal-stripped calf serum, and then they were treated with various concentrations of 17beta-estradiol as well as selective estrogen receptor (ER) modulators, raloxifene and tamoxifen. MCP-1 messenger ribonucleic acid (mRNA) levels were quantified by Northern blots. MCP-1 protein was quantified using an enzyme-linked immunosorbent assay. ER expression was evaluated by reverse transcriptase-polymerase chain reaction.
  
  
  RESULTS
  Human coronary artery smooth muscle cells expressed MCP-1 mRNA and produced MCP-1 protein. Estradiol induced up to 40% inhibition in mRNA expression at concentrations 10-9 M and higher. Raloxifene and tamoxifen also resulted in an inhibition, but the inhibition was less than when induced by estradiol. Estradiol also inhibited the MCP-1 protein production in a concentration-dependent manner (p < 0.05). Coronary smooth muscle cells expressed both ERalpha and ERbeta.
  
  
  CONCLUSIONS
  Our findings suggest that one of the mechanisms by which estrogen prevents atherosclerosis is by down-regulating MCP-1 expression, thus decreasing macrophage recruitment to the arterial wall.
authors.affiliation: Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut 6520-8063, USA.
authors.forename: E
authors.initials: E
authors.lastname: Seli
authors.forename: B
authors.initials: B
authors.lastname: Selam
authors.forename: G
authors.initials: G
authors.lastname: Mor
authors.forename: U A
authors.initials: UA
authors.lastname: Kayisli
authors.forename: T
authors.initials: T
authors.lastname: Pehlivan
authors.forename: A
authors.initials: A
authors.lastname: Arici
mesh_terms: D000818:Animals; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000209:etiology* / Q000276:immunology; D015152:Blotting, Northern; D002478:Cells, Cultured / Q000187:drug effects; D018932:Chemokine CCL2 / Q000032:analysis / Q000276:immunology*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D004958:Estradiol / Q000276:immunology* / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D020849:Raloxifene Hydrochloride / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D020845:Selective Estrogen Receptor Modulators / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D013629:Tamoxifen / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D018932:Chemokine CCL2; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D020849:Raloxifene Hydrochloride; D004958:Estradiol