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(Circulation Research. 2006;98:192.)
© 2006 American Heart Association, Inc.

Molecular Medicine

Downregulation of Endothelin-1 by Farnesoid X Receptor in Vascular Endothelial Cells

Fengtian He^*, Jiang Li^*, Ying Mu, Ramalinga Kuruba, Zheng Ma, Annette Wilson, Sean Alber, Yu Jiang, Troy Stevens, Simon Watkins, Bruce Pitt, Wen Xie, Song Li

From the Center for Pharmacogenetics and Department of Pharmaceutical Sciences (F.H., J.L., Y.M., R.K., Z.M., Y.J., W.X., S.L.), School of Pharmacy; Department of Environmental and Occupational Health (A.W., B.P.), Graduate School of Public Health; and Department of Cell Biology and Physiology (S.A., S.W.), School of Medicine, University of Pittsburgh, Pa; and Department of Pharmacology (T.S.), Center for Lung Biology, University of South Alabama, College of Medicine, Mobile, Ala.

Correspondence to Dr Song Li, Center for Pharmacogenetics, University of Pittsburgh, School of Pharmacy, 639 Salk Hall, Pittsburgh, PA 15261. E-mail Sol4{at}pitt.edu

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.

Key Words: farnesoid X receptor • bile acids • endothelin-1 • endothelial cells • gene regulation