Pregnane X Receptor regulates drug metabolism and transport in the vasculature and protects from oxidative stress.
Swales, KE, Moore, R, Truss, NJ, Tucker, A, Warner, TD, Negishi, M and Bishop-Bailey, D (2011) Pregnane X Receptor regulates drug metabolism and transport in the vasculature and protects from oxidative stress. Cardiovascular Research, 93 (4). 674 - 681. ISSN 0008-6363
Swales et al 2011.pdf - Published Version
Aims Circulating endogenous, dietary and foreign chemicals can contribute to vascular dysfunction. The mechanism by which the vasculature protects itself from these chemicals is unknown. This study investigates whether the pregnane X receptor (PXR), the major transcriptional regulator of hepatic drug metabolism and transport that responds to such xenobiotics, mediates vascular protection by co-ordinating a defence gene program in the vasculature.Methods and Results PXR was detected in primary human and rat aortic endothelial and smooth muscle cells and blood vessels including human and rat aorta. Metabolic PXR target genes cytochrome P450 3A, 2B, 2C and glutathione-S-transferase mRNA and activity were induced by PXR ligands in rodent and human vascular cells and absent in the aortas from PXR null mice stimulated in vivo or in rat aortic smooth muscle cells expressing dominant negative PXR. Activation of aortic PXR by classical agonists had several protective effects; increased xenobiotic metabolism demonstrated by bio-activation of the pro-drug clopidogrel, which reduced adenosine diphosphate-induced platelet aggregation; increased expression of multidrug resistance protein 1, mediating chemical efflux from the vasculature; and protection from reactive oxygen species-mediated cell death.Conclusions PXR co-ordinately up-regulates drug metabolism, transport and anti-oxidant genes to protect the vasculature from endogenous and exogenous insults, thus representing a novel gatekeeper for vascular defence.
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|Divisions:||Faculty of Health and Medical Sciences > Biochemistry and Physiology|
|Depositing User:||Symplectic Elements|
|Date Deposited:||28 Jun 2012 09:13|
|Last Modified:||23 Sep 2013 19:11|
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