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    RXR Ligands Negatively Regulate Thrombosis and Hemostasis.

    Unsworth, Amanda J, Flora, Gagan D, Sasikumar, Parvathy, Bye, Alexander P, Sage, Tanya, Kriek, Neline, Crescente, Marilena and Gibbins, Jonathan M (2017) RXR Ligands Negatively Regulate Thrombosis and Hemostasis. Arteriosclerosis, Thrombosis, and Vascular Biology, 37 (5). pp. 812-822. ISSN 1079-5642

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    Abstract

    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.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.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.

    Item Type: Article
    Peer-reviewed: Yes
    Date Deposited: 08 Mar 2019 08:56
    Publisher: American Heart Association
    Additional Information: This is an Open Access article published in the journal Arteriosclerosis, Thrombosis, and Vascular Biology by the American Heart Association.
    Divisions: Faculties > Science and Engineering
    Subject terms: Blood Platelets, Animals, Humans, Mice, Thrombosis, Disease Models, Animal, Microfilament Proteins, Thrombin, Cyclic AMP-Dependent Protein Kinases, NF-kappa B, Cell Adhesion Molecules, Platelet Membrane Glycoproteins, Phosphoproteins, Retinoid X Receptors, Cyclic AMP, Fibrinolytic Agents, Platelet Aggregation Inhibitors, Ligands, Second Messenger Systems, Calcium Signaling, Enzyme Activation, Phosphorylation, Hemostasis, Blood Coagulation, Platelet Activation, Dose-Response Relationship, Drug, Time Factors, Male, atherosclerosis, eczema, platelet activation, thrombin, Animals, Blood Coagulation, Blood Platelets, Calcium Signaling, Cell Adhesion Molecules, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Disease Models, Animal, Dose-Response Relationship, Drug, Enzyme Activation, Fibrinolytic Agents, Hemostasis, Humans, Ligands, Male, Mice, Microfilament Proteins, NF-kappa B, Phosphoproteins, Phosphorylation, Platelet Activation, Platelet Aggregation Inhibitors, Platelet Membrane Glycoproteins, Retinoid X Receptors, Second Messenger Systems, Thrombin, Thrombosis, Time Factors, Blood Platelets, Animals, Humans, Mice, Thrombosis, Disease Models, Animal, Microfilament Proteins, Thrombin, Cyclic AMP-Dependent Protein Kinases, NF-kappa B, Cell Adhesion Molecules, Platelet Membrane Glycoproteins, Phosphoproteins, Retinoid X Receptors, Cyclic AMP, Fibrinolytic Agents, Platelet Aggregation Inhibitors, Ligands, Second Messenger Systems, Calcium Signaling, Enzyme Activation, Phosphorylation, Hemostasis, Blood Coagulation, Platelet Activation, Dose-Response Relationship, Drug, Time Factors, Male, Cardiovascular System & Hematology, 1103 Clinical Sciences, 1102 Cardiorespiratory Medicine and Haematology
    URI: https://e-space.mmu.ac.uk/id/eprint/622580
    DOI: https://doi.org/10.1161/ATVBAHA.117.309207
    ISSN 1079-5642

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