Journal article
Non-genomic effects of the Pregnane X Receptor negatively regulate platelet functions, thrombosis and haemostasis
Scientific reports, Vol.9(1), pp.17210-14
11/20/2019
DOI: 10.1038/s41598-019-53218-x
PMCID: PMC6868193
PMID: 31748641
Abstract
The pregnane X receptor (PXR) is a nuclear receptor (NR), involved in the detoxification of xenobiotic compounds. Recently, its presence was reported in the human vasculature and its ligands were proposed to exhibit anti-atherosclerotic effects. Since platelets contribute towards the development of atherosclerosis and possess numerous NRs, we investigated the expression of PXR in platelets along with the ability of its ligands to modulate platelet activation. The expression of PXR in human platelets was confirmed using immunoprecipitation analysis. Treatment with PXR ligands was found to inhibit platelet functions stimulated by a range of agonists, with platelet aggregation, granule secretion, adhesion and spreading on fibrinogen all attenuated along with a reduction in thrombus formation (both in vitro and in vivo). The effects of PXR ligands were observed in a species-specific manner, and the human-specific ligand, SR12813, was observed to attenuate thrombus formation in vivo in humanised PXR transgenic mice. PXR ligand-mediated inhibition of platelet function was found to be associated with the inhibition of Src-family kinases (SFKs). This study identifies acute, non-genomic regulatory effects of PXR ligands on platelet function and thrombus formation. In combination with the emerging anti-atherosclerotic properties of PXR ligands, these anti-thrombotic effects may provide additional cardio-protective benefits.
Details
- Title: Subtitle
- Non-genomic effects of the Pregnane X Receptor negatively regulate platelet functions, thrombosis and haemostasis
- Creators
- Gagan D. Flora - University of ReadingKhaled A. Sahli - University of ReadingParvathy Sasikumar - University of ReadingLisa-Marie Holbrook - University of ReadingAlexander R. Stainer - University of ReadingSarah K. AlOuda - University of ReadingMarilena Crescente - University of ReadingTanya Sage - University of ReadingAmanda J. Unsworth - University of ReadingJonathan M. Gibbins - University of Reading
- Resource Type
- Journal article
- Publication Details
- Scientific reports, Vol.9(1), pp.17210-14
- DOI
- 10.1038/s41598-019-53218-x
- PMID
- 31748641
- PMCID
- PMC6868193
- NLM abbreviation
- Sci Rep
- ISSN
- 2045-2322
- eISSN
- 2045-2322
- Publisher
- NATURE PORTFOLIO
- Number of pages
- 14
- Grant note
- Felix Scholarship (2014-17) Saudi cultural bureau (London) RG/09/011/28094; RG/15/2/31224 / British Heart Foundation MR/J002666/1 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) MR/J002666/1 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) Biotechnology and Biological Sciences Research Council; UK Research & Innovation (UKRI); Biotechnology and Biological Sciences Research Council (BBSRC) RG/15/2/31224; RG/09/011/28094; PG/15/21/31355 / British Heart Foundation
- Language
- English
- Date published
- 11/20/2019
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984949185302771
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