ABSTRACT
Farnesoid X receptor (FXR) has been identified as an inhibitor of platelet function and an inducer of fibrinogen protein complex. However, the regulatory mechanism of FXR in hemostatic system remains incompletely understood. In this study, we aimed to investigate the functions of FXR in regulating antithrombin III (AT III). C57BL/6 mice and FXR knockout (FXR KO) mice were treated with or without GW4064 (30 mg/kg per day). FXR activation significantly prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT), lowered activity of activated factor X (FXa) and concentrations of thrombin-antithrombin complex (TAT) and activated factor II (FIIa), and increased level of AT III, whereas all of these effects were markedly reversed in FXR KO mice. In vivo, hepatic AT III mRNA and protein expression levels were up-regulated in wild-type mice after FXR activation, but down-regulated in FXR KO mice. In vitro study showed that FXR activation induced, while FXR knockdown inhibited, AT III expression in mouse primary hepatocytes. The luciferase assay and ChIP assay revealed that FXR can bind to the promoter region of AT III gene where FXR activation increased AT III transcription. These results suggest FXR activation inhibits coagulation process via inducing hepatic AT III expression in mice. The present study reveals a new role of FXR in hemostatic homeostasis and indicates that FXR might act as a potential therapeutic target for diseases related to hypercoagulation.
Subject(s)
Animals , Mice , Antithrombin III , Blood Coagulation , Hepatocytes , Liver , Mice, Inbred C57BL , Mice, Knockout , Receptors, Cytoplasmic and Nuclear/geneticsABSTRACT
The maintenance of human pregnancy and the initiation of parturition are closely related with the dynamic balance of the maternal-fetal immune microenvironment. Implantation of the blastocyst into the maternal decidua is the first step in pregnancy establishment, which is favored by the abundant blood flow and the immunotolerant microenvironment maintained by the balance of immune cells. The parturition resembles an inflammatory response that includes secretion of cytokines by resident and infiltrating immune cells into reproductive tissues and the maternal-fetal interface, which promotes the delivery of fetus from maternal organism. Therefore, the immune microenvironment in maternal-fetal interface regulates the critical steps of pregnancy and parturition. When the maternal-fetal immune microenvironment is imbalanced or impaired, miscarriage or preterm labor would happen. This article reviews the roles and mechanisms of several important immune cells in the maternal-fetal interface during the parturition and preterm labor.