title: Farnesoid x receptor ligands inhibit vascular smooth muscle cell inflammation and migration.
abstract: OBJECTIVE
  The farnesoid X receptor/bile acid receptor (FXR; NR1H4) is a ligand-activated transcription factor that regulates bile acid and lipid homeostasis, and is highly expressed in enterohepatic tissue. FXR is also expressed in vascular tissue. We have investigated whether FXR regulates inflammation and migration in vascular smooth muscle cells.
  
  
  RESULTS
  The FXR target gene, small heterodimer partner (SHP), was induced in vascular smooth muscle cells after treatment with synthetic FXR ligands, GW4064, or 6alpha-ethyl-chenodeoxycholic acid. FXR ligands induced smooth muscle cell death and downregulated interleukin (IL)-1beta-induced inducible nitric oxide synthase and cyclooxygenase-2 expression. In addition, FXR ligands suppressed smooth muscle cell migration stimulated by platelet-derived growth factor-BB. Reporter gene assays showed that FXR ligands activated an FXR reporter gene and suppressed IL-1beta-induced nuclear factor (NF)-kappaB activation and iNOS in a manner that required functional FXR and SHP.
  
  
  CONCLUSIONS
  Our observations suggest that a FXR-SHP pathway may be a novel therapeutic target for vascular inflammation, remodeling, and atherosclerotic plaque stability.
authors.affiliation: Centre of Translational Medicine & Therapeutics, William Harvey Research Institute, Barts & The London, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, United Kingdom.
authors.forename: Yoyo T Y
authors.initials: YT
authors.lastname: Li
authors.forename: Karen E
authors.initials: KE
authors.lastname: Swales
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Thomas
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Warner
authors.forename: David
authors.initials: D
authors.lastname: Bishop-Bailey
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000077214:Becaplermin; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects* / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D017930:Genes, Reporter; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D053583:Interleukin-1beta / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology*; D008024:Ligands; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000893:Anti-Inflammatory Agents; D000077214:Becaplermin; D002635:Chenodeoxycholic Acid; D051546:Cyclooxygenase 2; D004268:DNA-Binding Proteins; D053583:Interleukin-1beta; D007555:Isoxazoles; D008024:Ligands; D016328:NF-kappa B; D052247:Nitric Oxide Synthase Type II; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C099713:nuclear receptor subfamily 0, group B, member 2; C464660:obeticholic acid; C496318:Nos2 protein, rat; C496540:PTGS2 protein, human; C412815:GW 4064