title: FXR-mediated regulation of eNOS expression in vascular endothelial cells.
abstract: OBJECTIVE
  The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that is highly expressed in liver, kidney, adrenals, and intestine. FXR was previously proposed to play an important role in the pathogenesis of cardiovascular diseases via regulating the metabolism and transport of cholesterol. We have recently shown that FXR is also expressed in rat pulmonary vascular endothelial cells (EC) and that activation of FXR leads to inhibition of endothelin-1 expression. In the present study, we examine whether activation of FXR also affects the expression of endothelial nitric oxide synthase (eNOS) in rat, bovine, and sheep vascular EC.
  
  
  RESULTS
  Treatment of vascular EC with a FXR ligand resulted in upregulation of expression of eNOS mRNA and protein and an increased production of nitrite/nitrate. FXR appears to induce eNOS expression at a transcriptional level because (1) upregulation of eNOS mRNA expression was abolished by the treatment of a transcription inhibitor, actinomycin D; and (2) eNOS promoter activity was significantly increased by pharmacological or genetic activation of FXR. Functional analysis of rat eNOS promoter identified an imperfect inverted repeat DNA motif, IR2 (-628AGCTCAgtGGACCT-641), as a likely FXR-responsive element that is involved in eNOS regulation.
  
  
  CONCLUSIONS
  These results support the notion that vascular FXR may serve as a novel molecular target for manipulating the expression of eNOS for the treatment of vascular diseases.
authors.affiliation: Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, 639 Salk Hall, Pittsburgh, PA 15261, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Li
authors.forename: Annette
authors.initials: A
authors.lastname: Wilson
authors.forename: Ramalinga
authors.initials: R
authors.lastname: Kuruba
authors.forename: Qiuhong
authors.initials: Q
authors.lastname: Zhang
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: Fengtian
authors.initials: F
authors.lastname: He
authors.forename: Li-Ming
authors.initials: LM
authors.lastname: Zhang
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Pitt
authors.forename: Wen
authors.initials: W
authors.lastname: Xie
authors.forename: Song
authors.initials: S
authors.lastname: Li
mesh_terms: D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000819:agonists / Q000502:physiology*; D042783:Endothelial Cells / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic; D009569:Nitric Oxide / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000502:physiology*; D020218:Response Elements / Q000502:physiology; D012756:Sheep; D014157:Transcription Factors / Q000819:agonists / Q000502:physiology*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D004247:DNA; D004268:DNA-Binding Proteins; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated