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Turbidimetry on Human Washed Platelets: The Effect of the Pannexin1-inhibitor Brilliant Blue FCF on Collagen-induced Aggregation
Published on: April 6, 2017
Farnesoid X Receptor and Its Ligands Inhibit the Function of Platelets
Leonardo A Moraes1,2, Amanda J Unsworth1, Sakthivel Vaiyapuri3
1Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, Harborne Building, University of Reading, Reading, Berkshire, RG6 6AS, UK.
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.
Insights
Farnesoid X receptor (FXR) ligands inhibit platelet activation through DNA-independent mechanisms. This suggests FXR is a potential therapeutic target for preventing atherothrombotic disease.
Area of Science:
- * Hematology
- * Molecular Biology
- * Pharmacology
Background:
- * Platelets, although anucleated, possess transcription factors regulating function via DNA-independent pathways.
- * Farnesoid X receptor (FXR), a bile acid receptor, is identified as a key transcription factor in platelets.
- * FXR ligands, such as GW4064, are known to modulate cellular functions.
Purpose of the Study:
- * To investigate the presence and function of FXR in human platelets.
- * To determine the effect of FXR ligands on platelet activation and signaling pathways.
- * To explore the potential of FXR as a therapeutic target for atherothrombotic diseases.
Main Methods:
- * Human platelets were treated with FXR ligands (GW4064 and 6α-ethyl-chenodeoxycholic acid).
- * Platelet activation markers (calcium mobilization, secretion, aggregation, integrin signaling) were assessed.
- * FXR-deficient mouse platelets were used to confirm FXR-specific effects.
- * Cyclic guanosine monophosphate (cGMP) levels and downstream signaling were analyzed.
Main Results:
- * FXR is present in human platelets and its ligands inhibit platelet activation.
- * FXR ligands reduced platelet aggregation, calcium mobilization, and integrin signaling.
- * FXR activation modulated platelet cGMP levels and associated inhibitory signaling.
- * FXR-deficient mouse platelets were unresponsive to FXR agonists, confirming FXR's role.
Conclusions:
- * FXR ligands demonstrate significant antiplatelet effects through nongenomic mechanisms.
- * FXR plays a crucial role in regulating platelet function and signaling.
- * FXR represents a promising therapeutic target for preventing atherothrombotic disease due to its antiplatelet properties.
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