title: Impact of statins on modulation by insulin of expression of plasminogen activator inhibitor type-1.
abstract: OBJECTIVE
  Plasminogen activator inhibitor type-1 (PAI-1) is a physiologic inhibitor of fibrinolysis and a known determinant of cardiovascular risk. That its expression is stimulated by insulin in HepG2 human hepatoma cells has been shown earlier. Others have found that increased expression of PAI-1 is a risk factor for acute myocardial infarction. Pleiotropic (noncholesterol lowering) effects of statins seem to reduce cardiovascular risk. This study was designed to determine whether insulin stimulation of PAI-1 expression is attenuated by statins, and if so to explore mechanisms that are responsible for the attenuation.
  
  
  METHODS
  PAI-1 protein in the conditioned media was assayed by western blotting, and PAI-1 mRNA expression was measured by real-time reverse transcriptase polymerase chain reactions.
  
  
  RESULTS
  Insulin (0.001-10 micromol/l) increased accumulation of PAI-1 protein in the conditioned media and PAI-1 mRNA expression in HepG2 cells. A transient transfection assay of the human PAI-1 promoter-luciferase construct demonstrated that insulin increased PAI-1 promoter activity. Increased PAI-1 mRNA was attenuated significantly by U0126 and PD98059, specific inhibitors of mitogen-activated protein kinase. In contrast, GF109203X, an inhibitor of the protein kinase C pathway, and LY294002, an inhibitor of phosphatidylinositol 3-kinase, exerted no effects. Simvastatin (10 micromol/l), known to translocate membrane-bound sterol regulatory element-binding protein to nuclei, attenuated PAI-1 mRNA expression induced by insulin. It did not affect baseline PAI-1 mRNA expression. Intraperitoneal injection of insulin (0.1 IU/kg) increased concentrations of PAI-1 antigen in plasma in mice within 3 h, correlating with hepatic PAI-1 mRNA expression.
  
  
  CONCLUSIONS
  Insulin-mediated augmented expression of PAI-1 may be amenable to suppression attributable to pleiotropic effects of statins, potentially diminishing cardiovascular risk in patients with insulin resistance.
authors.affiliation: Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Sato
authors.forename: Jie
authors.initials: J
authors.lastname: Dong
authors.forename: Shogo
authors.initials: S
authors.lastname: Imagawa
authors.forename: Naoki
authors.initials: N
authors.lastname: Ishimori
authors.forename: Tomoo
authors.initials: T
authors.lastname: Furumoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsutsui
authors.forename: Burton E
authors.initials: BE
authors.lastname: Sobel
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fujii
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005342:Fibrinolysis / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019821:Simvastatin / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D019821:Simvastatin