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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2606.)
© 2007 American Heart Association, Inc.

Vascular Biology

Farnesoid X Receptor Ligands Inhibit Vascular Smooth Muscle Cell Inflammation and Migration

Yoyo T.Y. Li; Karen E. Swales; Gareth J. Thomas; Timothy D. Warner; David Bishop-Bailey

From the Centre of Translational Medicine & Therapeutics (Y.T.Y.L., K.E.S., T.D.W., D.B.B.), William Harvey Research Institute, and the Tumour Biology Laboratory (G.J.T.), Cancer Research UK Clinical Centre, Barts & The London, Queen Mary University of London, UK.

Correspondence to Dr. David Bishop-Bailey, Centre of Translational Medicine & Therapeutics, William Harvey Research Institute, Barts & The London, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, United Kingdom, E-mail d.bishop-bailey{at}qmul.ac.uk

Objective— The farnesoid X receptor/bile acid receptor (FXR; NR1H4) is a ligand-activated transcription factor that regulates bile acid and lipid homeostasis, and is highly expressed in enterohepatic tissue. FXR is also expressed in vascular tissue. We have investigated whether FXR regulates inflammation and migration in vascular smooth muscle cells.

Methods and Results— The FXR target gene, small heterodimer partner (SHP), was induced in vascular smooth muscle cells after treatment with synthetic FXR ligands, GW4064, or 6-ethyl-chenodeoxycholic acid. FXR ligands induced smooth muscle cell death and downregulated interleukin (IL)-1β–induced inducible nitric oxide synthase and cyclooxygenase-2 expression. In addition, FXR ligands suppressed smooth muscle cell migration stimulated by platelet-derived growth factor-BB. Reporter gene assays showed that FXR ligands activated an FXR reporter gene and suppressed IL-1β–induced nuclear factor (NF)-B activation and iNOS in a manner that required functional FXR and SHP.

Conclusion— Our observations suggest that a FXR-SHP pathway may be a novel therapeutic target for vascular inflammation, remodeling, and atherosclerotic plaque stability.

FXR is expressed in vascular smooth muscle cells. Here we show that in addition to antiproliferative properties, activation of FXR inhibits inflammation and migration of vascular smooth muscle cells. FXR may therefore be a novel direct target for vascular disease.

Key Words: FXR • vascular smooth muscle • iNOS • COX-2 • cell migration

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