Downregulation of endothelin-1 by farnesoid X receptor in vascular endothelial cells.
The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that is highly expressed in liver, kidney, adrenals, and intestine. FXR may play an important role in the pathogenesis of cardiovascular diseases via regulating the metabolism and transport of cholesterol. In this study, we report that FXR is also expressed in rat pulmonary artery endothelial cells (EC), a "nonclassical" bile acid target tissue. FXR is functional in EC, as demonstrated by induction of its target genes such as small heterodimer partner (SHP) after treatment with chenodeoxycholic acid, a FXR agonist. Interestingly, activation of FXR in EC led to downregulation of endothelin (ET)-1 expression. Reporter assays showed that activation of FXR inhibited transcriptional activation of the human ET-1 gene promoter and also repressed the activity of a heterologous promoter driven by activator protein (AP)-1 response elements. Electrophoretic mobility-shift and chromatin immunoprecipitation assays indicated that FXR reduced the binding activity of AP-1 transcriptional factors, suggesting that FXR may suppress ET-1 expression via negatively interfering with AP-1 signaling. These studies suggest that FXR may play a role in endothelial homeostasis and may serve as a novel molecular target for manipulating ET-1 expression in vascular EC.
He
Fengtian
F
Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, School of Pharmacy, Pittsburgh, PA 15261, USA.
Li
Jiang
J
Mu
Ying
Y
Kuruba
Ramalinga
R
Ma
Zheng
Z
Wilson
Annette
A
Alber
Sean
S
Jiang
Yu
Y
Stevens
Troy
T
Watkins
Simon
S
Pitt
Bruce
B
Xie
Wen
W
Li
Song
S
D000818:Animals; D002478:Cells, Cultured; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000502:physiology*; D015536:Down-Regulation; D042783:Endothelial Cells / Q000737:chemistry / Q000378:metabolism*; D019332:Endothelin-1 / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D011401:Promoter Regions, Genetic; D011651:Pulmonary Artery / Q000737:chemistry; D011817:Rabbits; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D020218:Response Elements; D018808:Transcription Factor AP-1 / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology*; D015533:Transcriptional Activation; D000099150:Receptor, Farnesoid X-Activated
D002635:Chenodeoxycholic Acid; D004268:DNA-Binding Proteins; D019332:Endothelin-1; D018160:Receptors, Cytoplasmic and Nuclear; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C099713:nuclear receptor subfamily 0, group B, member 2