Journal article
RXR Ligands Negatively Regulate Thrombosis and Hemostasis
Arteriosclerosis, thrombosis, and vascular biology, Vol.37(5), pp.812-822
05/01/2017
DOI: 10.1161/ATVBAHA.117.309207
PMCID: PMC5405776
PMID: 28254816
Abstract
Objective-Platelets have been found to express intracellular nuclear receptors including the retinoid X receptors (RXR alpha and RXR beta). 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 alpha IIb beta 3 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 alpha IIb beta 3 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 kappa-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.
Details
- Title: Subtitle
- RXR Ligands Negatively Regulate Thrombosis and Hemostasis
- Creators
- Amanda J. Unsworth - University of ReadingGagan D. Flora - University of ReadingParvathy Sasikumar - University of ReadingAlexander P. Bye - University of ReadingTanya Sage - University of ReadingNeline Kriek - University of ReadingMarilena Crescente - University of ReadingJonathan M. Gibbins - University of Reading
- Resource Type
- Journal article
- Publication Details
- Arteriosclerosis, thrombosis, and vascular biology, Vol.37(5), pp.812-822
- DOI
- 10.1161/ATVBAHA.117.309207
- PMID
- 28254816
- PMCID
- PMC5405776
- NLM abbreviation
- Arterioscler Thromb Vasc Biol
- ISSN
- 1079-5642
- eISSN
- 1524-4636
- Publisher
- Lippincott Williams & Wilkins
- Number of pages
- 25
- Grant note
- MR/J002666/1 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) RG/09/011/28094; RG/15/2/31224; PG/15/21/31355 / British Heart Foundation FS/11/86/29137; PG/15/21/31355; RG/09/011/28094; RG/15/2/31224 / British Heart Foundation Felix Scholarship MR/J002666/1 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC)
- Language
- English
- Date published
- 05/01/2017
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984949177302771
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