Li Yoyo T Y, Swales Karen E, Thomas Gareth J, Warner Timothy D, Bishop-Bailey David
Centre of Translational Medicine & Therapeutics, William Harvey Research Institute, Barts & The London, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, United Kingdom.
Arterioscler Thromb Vasc Biol. 2007 Dec;27(12):2606-11. doi: 10.1161/ATVBAHA.107.152694.
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.
The FXR target gene, small heterodimer partner (SHP), was induced in vascular smooth muscle cells after treatment with synthetic FXR ligands, GW4064, or 6alpha-ethyl-chenodeoxycholic acid. FXR ligands induced smooth muscle cell death and downregulated interleukin (IL)-1beta-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-1beta-induced nuclear factor (NF)-kappaB activation and iNOS in a manner that required functional FXR and SHP.
Our observations suggest that a FXR-SHP pathway may be a novel therapeutic target for vascular inflammation, remodeling, and atherosclerotic plaque stability.
法尼醇X受体/胆汁酸受体（FXR；NR1H4）是一种配体激活的转录因子，可调节胆汁酸和脂质稳态，在肠肝组织中高度表达。FXR在血管组织中也有表达。我们研究了FXR是否调节血管平滑肌细胞的炎症和迁移。
用合成FXR配体GW4064或6α-乙基鹅去氧胆酸处理后，血管平滑肌细胞中FXR靶基因小异二聚体伴侣（SHP）被诱导表达。FXR配体诱导平滑肌细胞死亡，并下调白细胞介素（IL）-1β诱导的诱导型一氧化氮合酶和环氧化酶-2的表达。此外，FXR配体抑制血小板衍生生长因子-BB刺激的平滑肌细胞迁移。报告基因分析表明，FXR配体激活FXR报告基因，并以需要功能性FXR和SHP的方式抑制IL-1β诱导的核因子（NF）-κB激活和诱导型一氧化氮合酶。
我们的观察结果表明，FXR-SHP途径可能是血管炎症、重塑和动脉粥样硬化斑块稳定性的新型治疗靶点。
