title: Effect of simvastatin on transforming growth factor beta-1-induced myofibroblast differentiation and collagen production in nasal polyp-derived fibroblasts.
abstract: BACKGROUND
  Statins are the most commonly prescribed drugs for the treatment of hypercholesterolemia. Statins exert not only lipid-lowering but also other cellular effects, including antifibrotic properties. The purpose of this study was to determine the effect of simvastatin  on transforming growth factor (TGF)-beta-1-induced myofibroblast differentiation and collagen production in nasal polyp-derived fibroblasts (NPDFs) and to verify the mechanism of the effect of simvastatin in TGF-beta-1-induced myofibroblast differentiation in NPDFs.
  
  
  METHODS
  NPDFs were pretreated with simvastatin with or without mevalonate or Y-27643 for 2 hours before induction by TGF-beta-1. The expression of alpha-smooth muscle actin (SMA) and collagen type IV mRNA was determined by a reverse transcription-polymerase chain reaction,  and the expression of alpha-SMA protein was determined by immunofluorescent cytochemical staining. Total soluble collagen production was analyzed by the SirCol collagen dye-binding assay (Biocolor, Belfast, U.K.). Phosphorylation of Smad 2/3 was evaluated by Western blot analysis.
  
  
  RESULTS
  In TGF-beta-1-induced NPDFs, simvastatin significantly inhibited the expressions of α-SMA and collagen type IV mRNA and reduced alpha-SMA and collagen protein levels. Pretreatment with mevalonate reversed the effect of simvastatin. The expression of alpha-SMA  mRNA and protein was significantly decreased by pretreatment with Y-27632. The TGF-beta-1-induced expression of pSmad 2/3 protein was notably decreased by pretreatment with simvastatin.
  
  
  CONCLUSIONS
  We showed that simvastatin inhibits TGF-beta-1-induced myofibroblast  differentiation (expression of alpha-SMA) and collagen production in NPDFs and Rho/Rock and TGF-β/Smad signaling is involved as an underlying mechanism. The results of our study suggest that simvastatin is a possible candidate for the suppression of nasal polyp formation.
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Guro Hospital, Korea University College of Medicine, Seoul, South Korea.
authors.forename: Il-Ho
authors.initials: IH
authors.lastname: Park
authors.forename: Se-Jin
authors.initials: SJ
authors.lastname: Park
authors.forename: Jung-Sun
authors.initials: JS
authors.lastname: Cho
authors.forename: You-Mi
authors.initials: YM
authors.lastname: Moon
authors.forename: Jun-Hyeok
authors.initials: JH
authors.lastname: Moon
authors.forename: Tae Hoon
authors.initials: TH
authors.lastname: Kim
authors.forename: Sang Hag
authors.initials: SH
authors.lastname: Lee
authors.forename: Heung-Man
authors.initials: HM
authors.lastname: Lee
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000577:Amides / Q000494:pharmacology; D000933:Antifibrinolytic Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D008798:Mevalonic Acid / Q000494:pharmacology; D058628:Myofibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009298:Nasal Polyps / Q000188:drug therapy* / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology*; D051899:Smad2 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D000577:Amides; D000933:Antifibrinolytic Agents; D004791:Enzyme Inhibitors; D011725:Pyridines; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1; C108830:Y 27632; D003094:Collagen; D019821:Simvastatin; D054460:rho-Associated Kinases; D008798:Mevalonic Acid