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Non-genomic effects of the Pregnane X Receptor negatively regulate platelet functions, thrombosis and haemostasis

Flora, G. D., Sahli, K. A., Sasikumar, P., Holbrook, L.-M., Stainer, A. R., Alouda, S. K., Crescente, M., Sage, T., Unsworth, A. J. and Gibbins, J. M. (2019) Non-genomic effects of the Pregnane X Receptor negatively regulate platelet functions, thrombosis and haemostasis. Scientific Reports, 9 (1). 17210. ISSN 2045-2322

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To link to this item DOI: 10.1038/s41598-019-53218-x

Abstract/Summary

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.

Item Type:Article
Refereed:Yes
Divisions:Interdisciplinary centres and themes > Institute for Cardiovascular and Metabolic Research (ICMR)
Faculty of Life Sciences > School of Biological Sciences > Biomedical Sciences
ID Code:87042
Publisher:Nature Publishing Group

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