Downregulation of endothelin-1 by farnesoid X receptor in vascular endothelial cells
Downregulation of endothelin-1 by farnesoid X receptor in vascular endothelial cells
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DOI：
10.1161/01.res.0000200400.55539.85
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发表时间：
2006-02-03
影响因子：
20.1
通讯作者：
Li, S
中科院分区：
文献类型：
--
作者：
He, FT;Li, J;Li, S
法尼醇 X 受体 (FXR) 是核受体超家族的成员，在肝脏、肾脏、肾上腺和肠道中高表达。 FXR可能通过调节胆固醇的代谢和转运在心血管疾病的发病机制中发挥重要作用。在这项研究中，我们报告 FXR 也在大鼠肺动脉内皮细胞 (EC) 中表达，这是一种“非经典”胆汁酸靶组织。 FXR 在 EC 中发挥功能，用 FXR 激动剂鹅去氧胆酸处理后诱导其靶基因（例如小异二聚体伴侣 (SHP)）就证明了这一点。有趣的是，EC 中 FXR 的激活导致内皮素 (ET)-1 表达下调。报告基因检测表明，FXR 的激活抑制了人类 ET-1 基因启动子的转录激活，并且还抑制了由激活蛋白 (AP)-1 响应元件驱动的异源启动子的活性。电泳迁移率变化和染色质免疫沉淀分析表明 FXR 降低了 AP-1 转录因子的结合活性，表明 FXR 可能通过负面干扰 AP-1 信号传导来抑制 ET-1 表达。这些研究表明 FXR 可能在内皮稳态中发挥作用，并可能作为操纵血管 EC 中 ET-1 表达的新分子靶点。
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.