Statins Modulate Cyclooxygenase-2 and Microsomal Prostaglandin E Synthase-1 in Human Hepatic Myofibroblasts
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Wiley-Liss Inc.
Abstract
Statins have been shown to exert anti-inflammatory and anti-fibrogenic properties in the liver. In the present study, we explored the mechanisms underlying anti-fibrogenic effects of statins in isolated hepatic myofibroblasts and focused on cyclooxyegnase-2, a major anti-proliferative pathway in these cells. We show that simvastatin and fluvastatin inhibit thymidine incorporation in hMF in a dose-dependent manner. Pretreatment of cells with NS398, a COX-2 inhibitor, partially blunted this effect. cAMP levels, essential to the inhibition of hMF proliferation, were increased by statins and inhibited by non-steroidal anti-inflammatory drugs. Since statins modify prenylation of some important proteins in gene expression, we investigated the targets involved using selective inhibitors of prenyltransferases. Inhibition of geranylgeranylation resulted in the induction of COX-2 and mPGES-1. Using gel retardation assays, we further demonstrated that statins potentially activated the NFκB and CRE/E-box binding for COX-2 promoter and the binding of GC-rich regions and GATA for mPGES-1. Together these data demonstrate that statin limit hepatic myofibroblasts proliferation via a COX-2 and mPGES-1 dependent pathway. These data suggest that statin-dependent increase of prostaglandin in hMF contributes to its anti-fibrogenic effect. © 2015 Wiley Periodicals, Inc.
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Cell gowth, Cyclooxygenase-2, Geranylgeranylation, Liver, Prostaglandin e2, Statin, Transcription factors, Blotting, western, Cell proliferation, Cells, cultured, Cyclic amp, Cyclic amp response element-binding protein, Cyclooxygenase 2, Cyclooxygenase inhibitors, Fatty acids, monounsaturated, Gata transcription factors, Gene expression regulation, enzymologic, Humans, Hydroxymethylglutaryl-coa reductase inhibitors, Indoles, Myofibroblasts, Nf-kappa b, Nitrobenzenes, Promoter regions, genetic, Prostaglandin-e synthases, Protein binding, Reverse transcriptase polymerase chain reaction, Simvastatin, Sulfonamides, Antifibrotic agent, Cre recombinase, Dimethylallyltransferase, Fluindostatin, Ibuprofen, Immunoglobulin enhancer binding protein, Messenger rna, N (2 cyclohexyloxy 4 nitrophenyl)methanesulfonamide, Prostaglandin e synthase 1, Prostaglandin e2, Prostaglandin e2 synthase 1, Thymidine, Transcription factor gata, Unclassified drug, Cyclic amp responsive element binding protein, Hydroxymethylglutaryl coenzyme a reductase inhibitor, Indole derivative, Monounsaturated fatty acid, N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide, Nitrobenzene derivative, Prostaglandin e synthase, Prostaglandin synthase inhibitor, Ptges protein, human, Sulfonamide, Antifibrotic activity, Article, Binding site, Cell function, Cell growth, Cell level, Complex formation, Concentration response, Controlled study, Dna protein complex, Dna synthesis, Drug activity, E box element, Enzyme activation, Enzyme inhibition, Gene expression, Gene expression regulation, Growth inhibition, Human, Human cell, Isoprenylation, Liver cell, Myofibroblast, Priority journal, Protein dna binding, Protein expression, Protein function, Protein induction, Protein localization, Protein prenylation, Protein synthesis, Signal transduction, Transcription regulation, Upregulation, Cell culture, Cytology, Drug effects, Genetics, Metabolism, Promoter region, Reverse transcription polymerase chain reaction, Western blotting