Cardiovascular Research Advance Access first published online on September 19, 2007
This version [Corrected Proof] published online on October 19, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm016
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FXR-mediated regulation of eNOS expression in vascular endothelial cells
1 Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, 639 Salk Hall, Pittsburgh, PA 15261, USA
2 Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
3 Department of Anesthesiology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
* Corresponding author. Tel: +1 412 383 7976; fax: +1 412 648 1664. E-mail address: sol4{at}pitt.edu
Aims: 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.
Methods and 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.
Conclusion: 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.
KEYWORDS Endothelial cells; Endothelial nitric oxide synthase; Farnesoid X receptor; Gene regulation
Time for primary review: 21 days
These authors contributed equally to this work.
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