RXR Ligands Negatively Regulate Thrombosis and Hemostasis.
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 and the underlying mechanism have not been fully characterized.


APPROACH AND RESULTS
The effect of 9-cis-retinoic acid, docosahexaenoic acid and methoprene acid on collagen receptor (glycoprotein VI [GPVI]) agonists and thrombin-stimulated platelet function; including aggregation, granule secretion, integrin activation, calcium mobilization, integrin αIIbβ3 outside-in signaling and thrombus formation in vitro and in vivo were determined. Treatment of platelets with RXR ligands resulted in attenuation of platelet functional responses after stimulation by GPVI agonists or thrombin and inhibition of integrin αIIbβ3 outside-in signaling. Treatment with 9-cis-retinoic acid caused inhibition of thrombus formation in vitro and an impairment of thrombosis and hemostasis 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 nuclear factor κ-light-chain-enhancer of activated B cell 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 protein kinase A, a known negative regulator of many aspects of platelet function. This mechanism may offer a possible explanation for the cardioprotective effects described in vivo after treatment with RXR ligands.
['Unsworth|Amanda J|AJ|', 'Flora|Gagan D|GD|', 'Sasikumar|Parvathy|P|', 'Bye|Alexander P|AP|', 'Sage|Tanya|T|', 'Kriek|Neline|N|', 'Crescente|Marilena|M|', 'Gibbins|Jonathan M|JM|']
D000818:Animals D001777:Blood Coagulation D001792:Blood Platelets D020013:Calcium Signaling D015815:Cell Adhesion Molecules D000242:Cyclic AMP D017868:Cyclic AMP-Dependent Protein Kinases D004195:Disease Models, Animal D004305:Dose-Response Relationship, Drug D004789:Enzyme Activation D005343:Fibrinolytic Agents D006487:Hemostasis D006801:Humans D008024:Ligands D008297:Male D051379:Mice D008840:Microfilament Proteins D016328:NF-kappa B D010750:Phosphoproteins D010766:Phosphorylation D015539:Platelet Activation D010975:Platelet Aggregation Inhibitors D010980:Platelet Membrane Glycoproteins D047488:Retinoid X Receptors D015290:Second Messenger Systems D013917:Thrombin D013927:Thrombosis D013997:Time Factors
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