title: Fenofibrate inhibits endothelin-1 expression by peroxisome proliferator-activated receptor α-dependent and independent mechanisms in human endothelial cells.
abstract: OBJECTIVE
  Dyslipidemia contributes to endothelial dysfunction in type 2 diabetes mellitus. Fenofibrate (FF), a ligand of the peroxisome proliferator-activated receptor-α (PPARα), has beneficial effects on microvascular complications. FF may act on the endothelium by regulating vasoactive factors, including endothelin-1 (ET-1). In vitro, FF decreases ET-1 expression in human microvascular endothelial cells. We investigated the molecular mechanisms involved in the effect of FF treatment on plasma levels of ET-1 in type 2 diabetes mellitus patients.
  
  
  RESULTS
  FF impaired the capacity of transforming growth factor-β to induce ET-1 gene expression. PPARα activation by FF increased expression of the transcriptional repressor Krüppel-like factor 11 and its binding to the ET-1 gene promoter. Knockdown of Krüppel-like factor 11 expression potentiated basal and transforming growth factor-β-stimulated ET-1 expression, suggesting that Krüppel-like factor 11 downregulates ET-1 expression. FF, in a PPARα-independent manner, and insulin enhanced glycogen synthase kinase-3β phosphorylation thus reducing glycogen synthase kinase-3 activity that contributes to the FF-mediated reduction of ET-1 gene expression. In type 2 diabetes mellitus, improvement of flow-mediated dilatation of the brachial artery by FF was associated with a decrease in plasma ET-1.
  
  
  CONCLUSIONS
  FF decreases ET-1 expression by a PPARα-dependent mechanism, via transcriptional induction of the Krüppel-like factor 11 repressor and by PPARα-independent actions via inhibition of glycogen synthase kinase-3 activity.
authors: Department of Pulmonary Immunity, Center for Infection and Immunity of Lille, Inserm U1019, CNRS UMR8204, Université Lille Nord de France, Lille, France. corine.glineur@pasteur-lille.fr
authors: Corine
authors: C
authors: Glineur
authors: Barbara
authors: B
authors: Gross
authors: Bernadette
authors: B
authors: Neve
authors: Corinne
authors: C
authors: Rommens
authors: Gerard T
authors: GT
authors: Chew
authors: Françoise
authors: F
authors: Martin-Nizard
authors: Fernando
authors: F
authors: Rodríguez-Pascual
authors: Santiago
authors: S
authors: Lamas
authors: Gerald F
authors: GF
authors: Watts
authors: Bart
authors: B
authors: Staels
mesh_terms: D051017:Apoptosis Regulatory Proteins; D001665:Binding Sites; D001916:Brachial Artery / Q000187:drug effects / Q000503:physiopathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D015536:Down-Regulation; D050171:Dyslipidemias / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D011345:Fenofibrate / Q000627:therapeutic use*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
chemical_list: D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D019332:Endothelin-1; D000960:Hypolipidemic Agents; C115117:KLF11 protein, human; D047493:PPAR alpha; D012097:Repressor Proteins; D016212:Transforming Growth Factor beta; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D011345:Fenofibrate