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- Title
Simvastatin inhibits transforming growth factor-β1-induced expression of type I collagen, CTGF, and α- SMA in keloid fibroblasts.
- Authors
Mun, Je‐Ho; Kim, Young‐Mi; Kim, Byung‐Soo; Kim, Jae‐Ho; Kim, Moon‐Bum; Ko, Hyun‐Chang
- Abstract
Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme- A reductase inhibitor, is used to reduce cholesterol levels. Accumulating evidence has revealed the immunomodulatory and anti-inflammatory effects of simvastatin that prevent cardiovascular diseases. In addition, the beneficial effects of statins on fibrosis of various organs have been reported. However, the functional effect of statins on dermal fibrosis of keloids has not yet been explored. The objective of this study was to determine whether simvastatin could affect dermal fibrosis associated with keloids. We examined the effect of simvastatin on transforming growth factor ( TGF)-β1-induced production of type I collagen, connective tissue growth factor ( CTGF or CCN2), and α-smooth muscle actin (α- SMA). Keloid fibroblasts were cultured and exposed to different concentrations of simvastatin in the presence of TGF-β1, and the effects of simvastatin on TGF-β1-induced collagen and CTGF production in keloid fibroblasts were determined. The type I collagen, CTGF, and α- SMA expression levels and the Smad2 and Smad3 phosphorylation levels were assessed by Western blotting. The effect of simvastatin on cell viability was evaluated by assessing the colorimetric conversion of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide. Simvastatin suppressed TGF-β1-induced type I collagen, CTGF, and α- SMA production in a concentration-dependent manner. The TGF-β1-induced Smad2 and Smad3 phosphorylation levels were abrogated by simvastatin pretreatment. The inhibition of type I collagen, CTGF, and α- SMA expression by simvastatin was reversed by geranylgeranyl pyrophosphate, suggesting that the simvastatin-induced cellular responses were due to inhibition of small GTPase Rho involvement. A Rho A activation assay showed that preincubation with simvastatin significantly blocked TGF-β1-induced Rho A activation. The Rho-associated coiled kinase inhibitor Y27632 abrogated TGF-β1-induced production of type I collagen, CTGF, and α- SMA. However, Y27632 had no significant effect on TGF-β1-induced phosphorylation of Smad2 and Smad3. In conclusion, the present study suggests that simvastatin is an effective inhibitor of TGF-β1-induced type I collagen, CTGF, and α- SMA production in keloid fibroblasts.
- Subjects
FIBROBLASTS; COLLAGEN; GENE expression; GROWTH factors; RESEARCH methodology; MULTIVARIATE analysis; RESEARCH funding; STATISTICS; T-test (Statistics); TISSUE culture; WESTERN immunoblotting; DATA analysis; DATA analysis software; DESCRIPTIVE statistics; SIMVASTATIN; KELOIDS; IN vitro studies; PHYSIOLOGY
- Publication
Wound Repair & Regeneration, 2014, Vol 22, Issue 1, p125
- ISSN
1067-1927
- Publication type
Article
- DOI
10.1111/wrr.12136