title: Upregulation of thrombomodulin expression by activation of farnesoid X receptor in vascular endothelial cells.
abstract: Thrombomodulin (TM) serves as a vasoprotective molecule on the surface of vascular endothelial cells (VECs) to maintain the endothelial microenvironment by suppressing cellular proliferation, adhesion and inflammatory responses. Farnesoid X receptor (FXR), a nuclear receptor (NR) and originally considered as a bile acid-activated transcriptional factor, not only regulates metabolism homeostasis, but also influences cholesterol transport, vascular tension, and inflammation. Recent studies have shown that TM expression is upregulated by several NRs. However, it is unknown whether there is a link between FXR and TM. Our studies demonstrated that TM expression and activity were up-regulated by FXR activation in VECs. Reporter assays showed that FXR activation significantly enhanced the transcriptional activity of human TM gene promoter. Elecrophoretic mobility-shift and chromatin immunoprecipitation assays indicated that FXR induced TM expression by binding to a novel FXR-responsive element (FXRE), an inverted repeat DNA motif, IR8 (-503 AGGTCCtcccaaagTGCCCT-484) in the promoter region of TM gene. These results suggest that FXR may serve as a novel molecular target for manipulating TM expression and activity in VECs, which may be helpful for designing the therapeutic strategies to the treatment of associated diseases by targeting FXR/TM pathway.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China.
authors.forename: Xie
authors.initials: X
authors.lastname: He
authors.forename: Zhizhen
authors.initials: Z
authors.lastname: Xu
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.forename: Yingru
authors.initials: Y
authors.lastname: Zheng
authors.forename: Wei
authors.initials: W
authors.lastname: Gong
authors.forename: Gang
authors.initials: G
authors.lastname: Huang
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.forename: Fengtian
authors.initials: F
authors.lastname: He
mesh_terms: D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism*; D020218:Response Elements / Q000187:drug effects / Q000235:genetics; D018180:Thrombomodulin / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear; D018180:Thrombomodulin; D000099150:Receptor, Farnesoid X-Activated
keywords: Farnesoid X receptor; Gene regulation; Inflammation; Thrombomodulin; Vascular endothelial cell