title: Effect of simvastatin on Kruppel-like factor2, endothelial nitric oxide synthase and thrombomodulin expression in endothelial cells under shear stress.
abstract: OBJECTIVE
  Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) and fluid wall shear stress have been reported to modulate the expression of genes related to inflammation, blood coagulation, thrombosis, and vascular constriction in cultured endothelial cells. In this study, we investigated the combined effect of laminar shear stress (LSS) and statins on endothelial cell gene expression.
  
  
  METHODS
  Kruppel-like factor 2 (KLF2), endothelial nitric oxide synthase (eNOS), and thrombomodulin (TM) mRNA and protein expression were evaluated in human abdominal aortic endothelial cells (HAAEC) treated with simvastatin (0.1, 1 or 10 microM) at various levels of LSS (0, 1.25, 12.5 or 25 dynes/cm(2)).
  
  
  RESULTS
  As expected, simvastatin and LSS separately enhanced KLF2, eNOS, and TM mRNA expressions. The combination of simvastatin and LSS resulted in significantly higher mRNA levels of all three genes compared to cells treated with LSS only. The highest KLF2, eNOS, and TM mRNA levels were detected at 10 microM simvastatin and 25 dynes/cm(2). Under these conditions, eNOS and TM protein levels were also elevated. Combining LSS and simvastatin produced an overall additive increase in KLF2, eNOS, and TM mRNA. Treatment of the endothelial cells with 10 microM simvastatin and 200 microM mevalonate completely eliminated the effect of simvastatin.
  
  
  CONCLUSIONS
  Our results suggest an additive increase in KLF2, eNOS, and TM expressions when simvastatin and LSS are combined. These results may help to explain the proposed non-lipid lowering benefits of statins observed in the clinic.
authors.affiliation: Dept. of Chemical Engineering, McGill University, 3610 University Street, Montreal, QC, Canada.
authors.forename: Joanna
authors.initials: J
authors.lastname: Rossi
authors.forename: Leonie
authors.initials: L
authors.lastname: Rouleau
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Tardif
authors.forename: Richard L
authors.initials: RL
authors.lastname: Leask
mesh_terms: D001012:Aorta, Abdominal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D051741:Kruppel-Like Transcription Factors / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D019821:Simvastatin / Q000008:administration & dosage / Q000494:pharmacology*; D013314:Stress, Mechanical; D018180:Thrombomodulin / Q000187:drug effects* / Q000235:genetics
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; D018180:Thrombomodulin; D019821:Simvastatin; D052250:Nitric Oxide Synthase Type III