title: Statins Modulate Cyclooxygenase-2 and Microsomal Prostaglandin E Synthase-1 in Human Hepatic Myofibroblasts.
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.
authors.affiliation: Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, PO Box 11-236 Beirut, Lebanon.|Department of Food Technologies, Al-Kafaat University, Ain Saadeh, Fanar, Lebanon.
authors.forename: Charbel A
authors.initials: CA
authors.lastname: Mouawad
authors.affiliation: Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, PO Box 11-236 Beirut, Lebanon.|Nehme and Therese Tohme Multiple Sclerosis Center-American University of Beirut Medical Center, Beirut, Lebanon.
authors.forename: May F
authors.initials: MF
authors.lastname: Mrad
authors.affiliation: Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, PO Box 11-236 Beirut, Lebanon.
authors.forename: Ghewa A
authors.initials: GA
authors.lastname: El-Achkar
authors.affiliation: Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, PO Box 11-236 Beirut, Lebanon.|Deparment of Immunology, University of Toronto, Canada.
authors.forename: Ali
authors.initials: A
authors.lastname: Abdul-Sater
authors.affiliation: Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, PO Box 11-236 Beirut, Lebanon.
authors.forename: Georges M
authors.initials: GM
authors.lastname: Nemer
authors.affiliation: iBiTec-S, Service de Pharmacologie et d'Immunoanalyse, CEA Saclay - Bât. 136, 91191 Gif-Sur-Yvette Cedex, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Creminon
authors.affiliation: Centre de Recherche sur l'Inflammation, INSERM UMR 1149, Paris, France.|Université Paris 7 Diderot, Sorbonne Paris Cité-Laboratoire d'excellence Inflamex, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, F-75018 Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lotersztajn
authors.affiliation: Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, PO Box 11-236 Beirut, Lebanon.|Centre de Recherche sur l'Inflammation, INSERM UMR 1149, Paris, France.|Université Paris 7 Diderot, Sorbonne Paris Cité-Laboratoire d'excellence Inflamex, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, F-75018 Paris, France.
authors.forename: Aïda
authors.initials: A
authors.lastname: Habib
mesh_terms: D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D000077340:Fluvastatin; D050980:GATA Transcription Factors / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D008099:Liver / Q000166:cytology; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D000071876:Prostaglandin-E Synthases / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019821:Simvastatin / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D016861:Cyclooxygenase Inhibitors; D005229:Fatty Acids, Monounsaturated; D050980:GATA Transcription Factors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D016328:NF-kappa B; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D000077340:Fluvastatin; D019821:Simvastatin; D000242:Cyclic AMP; D051546:Cyclooxygenase 2; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases
keywords: CELL GOWTH; CYCLOOXYGENASE-2; GERANYLGERANYLATION; LIVER; PROSTAGLANDIN E2; STATIN; TRANSCRIPTION FACTORS