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Arterioscler Thromb Vasc Biol. 2017 Aug;37(8):1482-1493. doi: 10.1161/ATVBAHA.117.309135. Epub 2017 Jun 15.

Farnesoid X Receptor and Liver X Receptor Ligands Initiate Formation of Coated Platelets.

Author information

1
From the Institute of Cardiovascular and Metabolic Research, School of Biological Sciences (A.J.U., A.P.B., N.K., T.S., M.C., C.I.J., J.M.G.) and Department of Food and Nutritional Sciences (D.S.T., P.Y.), University of Reading, United Kingdom; Oxford Haemophilia and Thrombosis Centre, Oxford Biomedical Research Centre, Churchill Hospital, United Kingdom (M.J.R.D.); Nuffield Division of Clinical Laboratory Sciences, University of Oxford, United Kingdom (M.J.R.D.); and Blizard Institute, Barts & the London School of Medicine & Dentistry, United Kingdom (H.E.A., M.C., T.D.W.).
2
From the Institute of Cardiovascular and Metabolic Research, School of Biological Sciences (A.J.U., A.P.B., N.K., T.S., M.C., C.I.J., J.M.G.) and Department of Food and Nutritional Sciences (D.S.T., P.Y.), University of Reading, United Kingdom; Oxford Haemophilia and Thrombosis Centre, Oxford Biomedical Research Centre, Churchill Hospital, United Kingdom (M.J.R.D.); Nuffield Division of Clinical Laboratory Sciences, University of Oxford, United Kingdom (M.J.R.D.); and Blizard Institute, Barts & the London School of Medicine & Dentistry, United Kingdom (H.E.A., M.C., T.D.W.). j.m.gibbins@reading.ac.uk.

Abstract

OBJECTIVES:

The liver X receptors (LXRs) and farnesoid X receptor (FXR) have been identified in human platelets. Ligands of these receptors have been shown to have nongenomic inhibitory effects on platelet activation by platelet agonists. This, however, seems contradictory with the platelet hyper-reactivity that is associated with several pathological conditions that are associated with increased circulating levels of molecules that are LXR and FXR ligands, such as hyperlipidemia, type 2 diabetes mellitus, and obesity.

APPROACH AND RESULTS:

We, therefore, investigated whether ligands for the LXR and FXR receptors were capable of priming platelets to the activated state without stimulation by platelet agonists. Treatment of platelets with ligands for LXR and FXR converted platelets to the procoagulant state, with increases in phosphatidylserine exposure, platelet swelling, reduced membrane integrity, depolarization of the mitochondrial membrane, and microparticle release observed. Additionally, platelets also displayed features associated with coated platelets such as P-selectin exposure, fibrinogen binding, fibrin generation that is supported by increased serine protease activity, and inhibition of integrin αIIbβ3. LXR and FXR ligand-induced formation of coated platelets was found to be dependent on both reactive oxygen species and intracellular calcium mobilization, and for FXR ligands, this process was found to be dependent on cyclophilin D.

CONCLUSIONS:

We conclude that treatment with LXR and FXR ligands initiates coated platelet formation, which is thought to support coagulation but results in desensitization to platelet stimuli through inhibition of αIIbβ3 consistent with their ability to inhibit platelet function and stable thrombus formation in vivo.

KEYWORDS:

bile; blood coagulation; blood platelets; calcium; cholesterol

PMID:
28619996
PMCID:
PMC5526435
DOI:
10.1161/ATVBAHA.117.309135
[Indexed for MEDLINE]
Free PMC Article

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