cyclic-gmp and obeticholic-acid

Although initially seemingly paradoxical because of the lack of nucleus, platelets possess many transcription factors that regulate their function through DNA-independent mechanisms. These include the farnesoid X receptor (FXR), a member of the superfamily of ligand-activated transcription factors, that has been identified as a bile acid receptor. In this study, we show that FXR is present in human platelets and FXR ligands, GW4064 and 6α-ethyl-chenodeoxycholic acid, modulate platelet activation nongenomically.. FXR ligands inhibited the activation of platelets in response to stimulation of collagen or thrombin receptors, resulting in diminished intracellular calcium mobilization, secretion, fibrinogen binding, and aggregation. Exposure to FXR ligands also reduced integrin α. This study provides support for the ability of FXR ligands to modulate platelet activation. The atheroprotective effects of GW4064, with its novel antiplatelet effects, indicate FXR as a potential target for the prevention of atherothrombotic disease.

Topics: Animals; Blood Platelets; Calcium Signaling; Chenodeoxycholic Acid; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Fibrinogen; Genotype; Hemostasis; Humans; Isoxazoles; Ligands; Mice, Inbred C57BL; Mice, Knockout; Phenotype; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Receptors, Cytoplasmic and Nuclear; Thrombosis; Time Factors