Simvastatin inhibits TGFβ1-induced fibronectin in human airway fibroblasts

Respiratory Research

Andrew J Halayko⁴  Jamila Chakir³  Michel Laviolette³  Eric Jacques³  Helmut Unruh⁵  Saeid Ghavami⁴  Mark M Mutawe¹  Karol D McNeill¹  Dedmer Schaafsma² 

[1] Biology of Breathing Theme, Manitoba Institute of Child Health, Winnipeg, MB, Canada;CIHR IMPACT Training Program in Pulmonary and Cardiovascular Research, University of Manitoba, Winnipeg, MB, Canada;Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Canada;CIHR National Training Program in Allergy and Asthma, University of Manitoba, Winnipeg, MB, Canada;Section of Thoracic Surgery, University of Manitoba, Winnipeg, MB, Canada

关键词: statins;    geranylgeranyl transferase;    fibronectin;    asthma;    airway remodeling;    airway fibroblasts;   

Others  :  796809
DOI  :  10.1186/1465-9921-12-113

 received in 2011-06-08, accepted in 2011-08-24,  发布年份 2011

【 摘 要 】

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.

【 授权许可】

   
2011 Schaafsma et al; licensee BioMed Central Ltd.

【 图 表 】

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