Abstract/Summary

OBJECTIVE: Platelets have been found to express intracellular nuclear receptors including the Retinoid X receptors (RXRα and RXRβ). Treatment of platelets with ligands of RXR has been shown to inhibit platelet responses to ADP and thromboxane A2, however the effects on responses to other platelet agonists as well as the underlying mechanism has not been fully characterised. APPROACH AND RESULTS: The effect of 9-cis-retinoic acid (9-cis-RA), docosahexaenoic acid and synthetic ligand for RXR, methoprene acid on collagen receptor (GPVI) agonists and Thrombin stimulated platelet function; including aggregation, granule secretion, integrin activation, calcium mobilisation, integrin αIIbβ3 outside-in signalling and thrombus formation in vitro and in vivo were determined. Treatment of platelets with RXR ligands resulted in attenuation of platelet functional responses following stimulation by GPVI agonists and thrombin and inhibition of integrin αIIbβ3 outside-in signalling. Treatment with 9-cis-RA caused inhibition of thrombus formation in vitro and an impairment of thrombosis and haemostasis in vivo. Both RXR ligands stimulated protein kinase A activation, measured by VASP S157 phosphorylation, that was found to be dependent on both cAMP and NFκB activity. CONCLUSIONS: This study identifies a widespread, negative regulatory role for RXR in the regulation of platelet functional responses and thrombus formation and describes novel events that lead to the upregulation of PKA, a known negative regulator of many aspects of platelet function. This mechanism may offer a possible explanation for the cardioprotective effects described in vivo following treatment with RXR ligands.