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Non-genomic effects of the Pregnane X Receptor (PXR) and Retinoid X Receptor (RXR) in platelets

Flora, G. D. (2018) Non-genomic effects of the Pregnane X Receptor (PXR) and Retinoid X Receptor (RXR) in platelets. PhD thesis, University of Reading

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Abstract/Summary

Background: The pregnane X receptor (PXR) is a nuclear receptor (NR) involved in the detoxification of xenobiotic compounds via upregulation of cytochrome P450 enzyme expression. Recently, the presence of PXR was reported in the human vasculature and its ligands were proposed to exhibit anti-atherosclerotic effects. The retinoid X receptor (RXR) is another NR that regulates numerous biological functions. RXR (α and β) is expressed in platelets, and its ligands have been reported to inhibit platelet function mediated by Gq coupled ADP and TXA2 receptors. Aims: Platelets play a substantial role towards the initiation of atherosclerosis and express numerous NRs. Given the anti-atherosclerotic effects of PXR ligands, we explored whether PXR is present in human platelets and evaluated the role of its ligands in regulating platelet activation in response to different platelet agonists. Since RXR is known to modulate platelet function in response to ADP and U46619, and is able to function in other cells in collaboration with PXR, we also sought to extend studies of the role of RXR in the modulation of platelet activation stimulated by collagen/CRP-XL or thrombin. Results: The expression of PXR in human platelets was confirmed using western blot and immunoprecipitation analysis. Platelets treated with PXR ligands (SR12813 or rifampicin) inhibited a range of platelet activities such as aggregation, fibrinogen binding to integrin αIIbβ3, degranulation, intracellular calcium mobilisation, integrin αIIbβ3 outside-in signalling. In the absence of nuclei, the actions of PXR are non-genomic in nature. Human and mouse PXR ligands reduced thrombus formation in vitro in human and mouse blood respectively. These effects of human and mouse PXR ligands were observed in a species-specific manner. Anti-thrombotic effects of SR12813 were observed in humanised PXR knock-in mice using an in vivo mouse model of thrombosis. In addition to the reduced tyrosine phosphorylation of multiple GPVI signalling components, caused by PXR ligands, inhibition of phosphorylation of Src family kinases (SFKs) proximal to GPVI, CLEC-2 and integrin αIIbβ3 receptor was also observed. This suggests SFKs as a potential target of PXR function. Furthermore, RXR ligands (9-cis-RA or methoprene acid), in a non-genomic manner, down-regulated platelet activity stimulated by collagen/CRP-XL or thrombin. RXR was found to exist in the form of a heterodimer with other NRs such as PXR, liver X receptor (LXR) and peroxisome proliferator-activated receptor (PPARβ and PPARγ). Exposure to 9-cis-RA also caused a reduction in thrombus formation in vitro and in vivo, with impairment of haemostatic response. Conclusions: This study identifies the ability of PXR and RXR to regulate platelet activation and thrombus formation in a non-genomic manner. The potential anti-atherosclerotic properties of PXR and RXR ligands, together with newly identified anti-thrombotic effects may provide additional cardio-protective benefits.

Item Type:Thesis (PhD)
Thesis Supervisor:Gibbins, J.
Thesis/Report Department:School of Biological Sciences
Identification Number/DOI:
Divisions:Interdisciplinary centres and themes > Institute for Cardiovascular and Metabolic Research (ICMR)
Faculty of Life Sciences > School of Biological Sciences > Biomedical Sciences
ID Code:80709

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