Leonardo A Moraes1,2, Amanda J Unsworth1, Jonathan M Gibbins1, Sakthivel Vaiyapuri3, Marfoua S Ali1, Parvathy Sasikumar1, Tanya Sage1, Gagan D Flora1, Alex P Bye1, Neline Kriek1, Emilie Dorchies4, Olivier Molendi-Coste4, David Dombrowicz4, Bart Staels4, David Bishop-Bailey5. 1. Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, Harborne Building, University of Reading, Reading, Berkshire, RG6 6AS, UK. 2. Department of Physiology & NUS Immunology Program, Centre for Life Sciences, Yong Loo Lin School of Medicine, National University of Singapore, 117456, Singapore. 3. School of Pharmacy, University of Reading, Reading, Berkshire, RG6 6UB, UK. 4. European Genomic Institute for Diabetes (EGID), F-59000, Lille, France; INSERM UMR1011, F-59000 Lille, France, University of Lille, F-59000 Lille, France; Institut Pasteur de Lille, F-59019 Lille, France. 5. Comparative Biomedical Sciences, Royal Veterinary College, University of London, London, NW1 OTU, UK.
Abstract
OBJECTIVE: 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. APPROACH AND RESULTS: 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 αIIbβ3 outside-in signaling and thereby reduced the ability of platelets to spread and to stimulate clot retraction. FXR function in platelets was found to be associated with the modulation of cyclic guanosine monophosphate levels in platelets and associated downstream inhibitory signaling. Platelets from FXR-deficient mice were refractory to the actions of FXR agonists on platelet function and cyclic nucleotide signaling, firmly linking the nongenomic actions of these ligands to the FXR. CONCLUSIONS: 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.
OBJECTIVE: 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. APPROACH AND RESULTS: 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 αIIbβ3 outside-in signaling and thereby reduced the ability of platelets to spread and to stimulate clot retraction. FXR function in platelets was found to be associated with the modulation of cyclic guanosine monophosphate levels in platelets and associated downstream inhibitory signaling. Platelets from FXR-deficient mice were refractory to the actions of FXR agonists on platelet function and cyclic nucleotide signaling, firmly linking the nongenomic actions of these ligands to the FXR. CONCLUSIONS: 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.
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