title: Simvastatin inhibits TGFβ1-induced fibronectin in human airway fibroblasts.
abstract: BACKGROUND
  Bronchial fibroblasts contribute to airway remodelling, including airway wall fibrosis. Transforming growth factor (TGF)-β1 plays a major role in this process. We previously revealed the importance of the mevalonate cascade in the fibrotic response of human airway smooth muscle cells. We now investigate mevalonate cascade-associated signaling in TGFβ1-induced fibronectin expression by bronchial fibroblasts from non-asthmatic and asthmatic subjects.
  
  
  METHODS
  We used simvastatin (1-15 μM) to inhibit 3-hydroxy-3-methlyglutaryl-coenzyme A (HMG-CoA) reductase which converts HMG-CoA to mevalonate. Selective inhibitors of geranylgeranyl transferase-1 (GGT1; GGTI-286, 10 μM) and farnesyl transferase (FT; FTI-277, 10 μM) were used to determine whether GGT1 and FT contribute to TGFβ1-induced fibronectin expression. In addition, we studied the effects of co-incubation with simvastatin and mevalonate (1 mM), geranylgeranylpyrophosphate (30 μM) or farnesylpyrophosphate (30 μM).
  
  
  RESULTS
  Immunoblotting revealed concentration-dependent simvastatin inhibition of TGFβ1 (2.5 ng/ml, 48 h)-induced fibronectin. This was prevented by exogenous mevalonate, or isoprenoids (geranylgeranylpyrophosphate or farnesylpyrophosphate). The effects of simvastatin were mimicked by GGTI-286, but not FTI-277, suggesting fundamental involvement of GGT1 in TGFβ1-induced signaling. Asthmatic fibroblasts exhibited greater TGFβ1-induced fibronectin expression compared to non-asthmatic cells; this enhanced response was effectively reduced by simvastatin.
  
  
  CONCLUSIONS
  We conclude that TGFβ1-induced fibronectin expression in airway fibroblasts relies on activity of GGT1 and availability of isoprenoids. Our results suggest that targeting regulators of isoprenoid-dependent signaling holds promise for treating airway wall fibrosis.
authors.affiliation: Department of Physiology, Section of Respiratory Disease, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Dedmer
authors.initials: D
authors.lastname: Schaafsma
authors.forename: Karol D
authors.initials: KD
authors.lastname: McNeill
authors.forename: Mark M
authors.initials: MM
authors.lastname: Mutawe
authors.forename: Saeid
authors.initials: S
authors.lastname: Ghavami
authors.forename: Helmut
authors.initials: H
authors.lastname: Unruh
authors.forename: Eric
authors.initials: E
authors.lastname: Jacques
authors.forename: Michel
authors.initials: M
authors.lastname: Laviolette
authors.forename: Jamila
authors.initials: J
authors.lastname: Chakir
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Halayko
mesh_terms: D000328:Adult; D056151:Airway Remodeling / Q000187:drug effects*; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001249:Asthma / Q000378:metabolism* / Q000473:pathology; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D008798:Mevalonic Acid / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D012717:Sesquiterpenes / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D055815:Young Adult
chemical_list: C096856:FTI 277; D005353:Fibronectins; C437105:GGTI 286; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; D053773:Transforming Growth Factor beta1; C004808:farnesyl pyrophosphate; D008715:Methionine; D019821:Simvastatin; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D051231:Farnesyltranstransferase; D007930:Leucine; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid