Upregulation of thrombomodulin expression by activation of farnesoid X receptor in vascular endothelial cells

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. Famesoid 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 sLudies 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. Elecrophorclic mobility shift and chromatin irnmunoprecipilarion assays indicated that FXR induced TM expression by binding to a novel FXR-responsive element (FXRE), an inverted repeal DNA motif, IR8 (-503 AGGTCCLcccaaagTGCCCT-484) in the promoter region of TM gene. These results suggest that FXR may serve as a novel molecular Larger 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. (C) 2013 Elsevier B.V. All tights reserved