Simvastatin inhibits TGFβ1-induced fibronectin in human airway fibroblasts

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dc.contributor.authorSchaafsma, Dedmer
dc.contributor.authorMcNeill, Karol D
dc.contributor.authorMutawe, Mark M
dc.contributor.authorGhavami, Saeid
dc.contributor.authorUnruh, Helmut
dc.contributor.authorJacques, Eric
dc.contributor.authorLaviolette, Michel
dc.contributor.authorChakir, Jamila
dc.contributor.authorHalayko, Andrew J
dc.date.accessioned2016-05-24T15:20:16Z
dc.date.available2016-05-24T15:20:16Z
dc.date.issued2011-08-24
dc.date.updated2016-05-20T16:03:14Z
dc.description.abstractAbstract 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.
dc.identifier.citationRespiratory Research. 2011 Aug 24;12(1):113
dc.identifier.urihttp://dx.doi.org/10.1186/1465-9921-12-113
dc.identifier.urihttp://hdl.handle.net/1993/31300
dc.language.rfc3066en
dc.rightsopen accessen_US
dc.rights.holderSchaafsma et al; licensee BioMed Central Ltd.
dc.titleSimvastatin inhibits TGFβ1-induced fibronectin in human airway fibroblasts
dc.typeJournal Article
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