Simvastatin Modulates Extracellular Matrix Assembly by Displaying an Antifibrotic Activity in Vitro

Abstract

Statins, competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, are known to possess properties beyond their cholesterol-lowering effect including anti-inflammatory, antiproliferative and anti-immunomodulatory effects. We examined the effect of simvastatin on extracellular matrix (ECM) assembly by human skin fibroblasts (HSFs) in vitro. Using collagen gel contraction (CGC) assay we showed that simvastatin inhibits contraction of type I collagen-rich gels in a dose-dependent manner. This effect of simvastatin could be overcome by co-incubating the cells with mevalonate. Actin staining revealed that inhibition of CGC by simvastatin is associated with diminished ability of the cells to form aggregates. Using whole human genome Illumina microarray we sought to search for new candidate genes whose expression is regulated by simvastatin during CGC and focused specifically on the genes related to ECM synthesis and remodeling. We found that simvastatin profoundly downregulated gene expression of 27 ECM molecules including proteoglycans decorin and versican, both of which are known to be essential constituents of proper ECM. Expression of these two molecules was further verified by Northern blot analysis. Finally, when simvastatin treated HSFs were activated with TGF-β1, the cell-mediated contraction of collagen gel was restored. Our results indicate that simvastatin markedly alters ECM assembly in vitro possessing an antifibrotic activity.