RXR Ligands Negatively Regulate Thrombosis and Hemostasis.
Arterioscler Thromb Vasc Biol
; 37(5): 812-822, 2017 05.
Article
em En
| MEDLINE
| ID: mdl-28254816
ABSTRACT
OBJECTIVE:
Platelets have been found to express intracellular nuclear receptors including the retinoid X receptors (RXRα and RXRß). 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 ANDRESULTS:
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 αIIbß3 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 αIIbß3 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.Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Trombose
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Plaquetas
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Inibidores da Agregação Plaquetária
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Ativação Plaquetária
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Receptores X de Retinoides
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Fibrinolíticos
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Hemostasia
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Arterioscler Thromb Vasc Biol
Assunto da revista:
ANGIOLOGIA
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Reino Unido