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Respiratory Research
Published in: Respiratory Research 1/2011

Open Access 01-12-2011 | Research

Simvastatin inhibits TGFβ1-induced fibronectin in human airway fibroblasts

Authors: Dedmer Schaafsma, Karol D McNeill, Mark M Mutawe, Saeid Ghavami, Helmut Unruh, Eric Jacques, Michel Laviolette, Jamila Chakir, Andrew J Halayko

Published in: Respiratory Research | Issue 1/2011

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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.
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Metadata
Title
Simvastatin inhibits TGFβ1-induced fibronectin in human airway fibroblasts
Authors
Dedmer Schaafsma
Karol D McNeill
Mark M Mutawe
Saeid Ghavami
Helmut Unruh
Eric Jacques
Michel Laviolette
Jamila Chakir
Andrew J Halayko
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2011
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/1465-9921-12-113

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Keynote webinar | Spotlight on medication adherence

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WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

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