Simvastatin inhibits transforming growth factor‐β1‐induced expression of type I collagen, CTGF, and α‐SMA in keloid fibroblasts

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 RhoA activation assay showed that preincubation with simvastatin significantly blocked TGF-β1-induced RhoA 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.

Local Application of Statins Significantly Reduced Hypertrophic Scarring in a Rabbit Ear Model

“…40 After injury, it continues to rise steadily through day 40, and blockade of CTGF mRNA by antisense oligonucleotides is associated with reduction of collagen types I and III and scarring. 35 Our results indicate that the scar reduction effect of statins is at least partly due to the decrease of CTGF expression, and consequently the decrease of collagen expression, which is consistent with Mun et al’s 41 in vitro study and Watts and Spiteri’s 12 in vivo study. Whether statin affected the expression of TGF-βRII is unclear in this study.…”

Simvastatin reduces fibrosis and protects against muscle weakness after massive rotator cuff tear

“…Consistent with this finding, there was a decrease in type I collagen expression of similar magnitude. In addition to directly downregulating type I collagen expression 29 , simvastatin can also indirectly regulate the ECM content of tissues by modulating MMP expression and activity levels. Aktas and colleagues 2 reported that simvastatin reduced the levels of MMP-3 in articular chondrocytes after induction of an ACL tear, and Yao 42 reported simvastatin decreased MMP-9 expression in the vasculature of rats with experimentally induced pulmonary hypertension.…”

Biological Differences between Hanwoo longissimus dorsi and semimembranosus Muscles in Collagen Synthesis of Fibroblasts

“…The biosynthetic pathway of collagen production is a very complex (Mun et al , 2014). Specific collagens are encoded by specific genes; COL1A1 an COL1A2 for type I collagen and COL3A1 for type III collagen, are may involve in the regulation of collagen synthesis in animal (Gonzalez et al , 2014).…”

“…The collagen biosynthesis is very complex; about 34 genes are involved in collagen formation. The cytokine and growth factors genes are involved to synthesis of both type I and type III collagen through phosphorylation of the downstream mediators, Smad2/3in fibroblasts (Mun et al , 2014). Other than this, apoptotic and heat shock proteins/genes are also involved in collagen synthesis has been unclear (Alikhani et al , 2005).…”