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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...

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Autores principales: Unsworth, Amanda J., Flora, Gagan D., Sasikumar, Parvathy, Bye, Alexander P., Sage, Tanya, Kriek, Neline, Crescente, Marilena, Gibbins, Jonathan M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5405776/
https://www.ncbi.nlm.nih.gov/pubmed/28254816
http://dx.doi.org/10.1161/ATVBAHA.117.309207
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author Unsworth, Amanda J.
Flora, Gagan D.
Sasikumar, Parvathy
Bye, Alexander P.
Sage, Tanya
Kriek, Neline
Crescente, Marilena
Gibbins, Jonathan M.
author_facet Unsworth, Amanda J.
Flora, Gagan D.
Sasikumar, Parvathy
Bye, Alexander P.
Sage, Tanya
Kriek, Neline
Crescente, Marilena
Gibbins, Jonathan M.
author_sort Unsworth, Amanda J.
collection PubMed
description 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.
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spelling pubmed-54057762017-10-11 RXR Ligands Negatively Regulate Thrombosis and Hemostasis Unsworth, Amanda J. Flora, Gagan D. Sasikumar, Parvathy Bye, Alexander P. Sage, Tanya Kriek, Neline Crescente, Marilena Gibbins, Jonathan M. Arterioscler Thromb Vasc Biol Basic Sciences 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. Lippincott Williams & Wilkins 2017-05 2017-03-02 /pmc/articles/PMC5405776/ /pubmed/28254816 http://dx.doi.org/10.1161/ATVBAHA.117.309207 Text en © 2017 The Authors. Arteriosclerosis, Thrombosis, and Vascular Biology is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
spellingShingle Basic Sciences
Unsworth, Amanda J.
Flora, Gagan D.
Sasikumar, Parvathy
Bye, Alexander P.
Sage, Tanya
Kriek, Neline
Crescente, Marilena
Gibbins, Jonathan M.
RXR Ligands Negatively Regulate Thrombosis and Hemostasis
title RXR Ligands Negatively Regulate Thrombosis and Hemostasis
title_full RXR Ligands Negatively Regulate Thrombosis and Hemostasis
title_fullStr RXR Ligands Negatively Regulate Thrombosis and Hemostasis
title_full_unstemmed RXR Ligands Negatively Regulate Thrombosis and Hemostasis
title_short RXR Ligands Negatively Regulate Thrombosis and Hemostasis
title_sort rxr ligands negatively regulate thrombosis and hemostasis
topic Basic Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5405776/
https://www.ncbi.nlm.nih.gov/pubmed/28254816
http://dx.doi.org/10.1161/ATVBAHA.117.309207
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