Farnesoid X Receptor and its ligands inhibit the function of platelets

Moraes, L. A., Unsworth, A. J., Vaiyapuri, S. ORCID: https://orcid.org/0000-0002-6006-6517, Ali, M. S., Sasikumar, P., Sage, T., Flora, G. D., Bye, A. P. ORCID: https://orcid.org/0000-0002-2061-2253, Kriek, N., Dorchies, E., Molendi-Coste, O., Dombrowicz, D., Staels, B., Bishop-Bailey, D. and Gibbins, J. M. ORCID: https://orcid.org/0000-0002-0372-5352 (2016) Farnesoid X Receptor and its ligands inhibit the function of platelets. Arteriosclerosis Thrombosis and Vascular Biology, 36 (12). pp. 2324-2333. ISSN 1524-4636 doi: 10.1161/ATVBAHA.116.308093

Abstract/Summary

Objective - While initially seemingly paradoxical due to the lack of nucleus, platelets possess a number of 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 6-ECDCA, 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 and secretion, fibrinogen binding and aggregation. Exposure to FXR ligands also reduced integrin alphaIIbbeta3 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 cGMP 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 non-genomic actions of these ligands to the FXR receptor. Conclusion – This study provides support for the ability of FXR ligands to modulate platelet activation. The athero-protective effects of GW4064, with its novel antiplatelet effects, indicate FXR as a potential target for prevention of athero-thrombotic disease.

Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/67335
Identification Number/DOI	10.1161/ATVBAHA.116.308093
Refereed	Yes
Divisions	Interdisciplinary centres and themes > Institute for Cardiovascular and Metabolic Research (ICMR) Life Sciences > School of Biological Sciences > Biomedical Sciences Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology
Uncontrolled Keywords	Platelets, Farnesoid X Receptor, nongenomic, transcription factor, signal transduction, haemostasis, thrombosis
Publisher	Lippincott, Williams & Wilkins
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