title: Shear stress activation of nuclear receptor PXR in endothelial detoxification.
abstract: Endothelial cells (ECs) are constantly exposed to xenobiotics and endobiotics or their metabolites, which perturb EC function, as well as to shear stress, which plays a crucial role in vascular homeostasis. Pregnane X receptor (PXR) is a nuclear receptor and a key regulator of the detoxification of xeno- and endobiotics. Here we show that laminar shear stress (LSS), the atheroprotective flow, activates PXR in ECs, whereas oscillatory shear stress, the atheroprone flow, suppresses PXR. LSS activation of PXR in cultured ECs led to the increased expression of a PXR target gene, multidrug resistance 1 (MDR1). An in vivo study using rats showed that the expression of MDR1 was significantly higher in the endothelium from the descending thoracic aorta, where flow is mostly laminar, than from the inner curvature of aortic arch, where flow is disturbed. Functionally, LSS-activated PXR protects ECs from apoptosis triggered by doxorubicin via the induction of MDR1 and other detoxification genes. PXR also suppressed the expression of proinflammatory adhesion molecules and monocyte adhesion in response to TNF-α and lipopolysaccharide. Overexpression of a constitutively active PXR in rat carotid arteries potently attenuated proinflammatory responses. In addition, cDNA microarray revealed a large number of the PXR-activated endothelial genes whose products are responsible for major steps of detoxification, including phase I and II metabolizing enzymes and transporters. These detoxification genes in ECs are induced by LSS in ECs in a PXR-dependent manner. In conclusion, our results indicate that PXR represents a flow-activated detoxification system to protect ECs against damage by xeno- and endobiotics.
authors.affiliation: Institute of Cardiovascular Science and Key Laboratory of Molecular Cardiology, Ministry of Education, Peking University, Beijing 100191, China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Wang
authors.forename: Xi
authors.initials: X
authors.lastname: Fang
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.forename: Zhen
authors.initials: Z
authors.lastname: Chen
authors.forename: Beilei
authors.initials: B
authors.lastname: Zhao
authors.forename: Lei
authors.initials: L
authors.lastname: Xiao
authors.forename: Ao
authors.initials: A
authors.lastname: Liu
authors.forename: Yi-Shuan J
authors.initials: YS
authors.lastname: Li
authors.forename: John Y-J
authors.initials: JY
authors.lastname: Shyy
authors.forename: Youfei
authors.initials: Y
authors.lastname: Guan
authors.forename: Shu
authors.initials: S
authors.lastname: Chien
authors.forename: Nanping
authors.initials: N
authors.lastname: Wang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002339:Carotid Arteries / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D065633:Cytochrome P-450 CYP1B1; D020869:Gene Expression Profiling; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D000077297:Pregnane X Receptor; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013314:Stress, Mechanical; D015262:Xenobiotics / Q000378:metabolism / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D015262:Xenobiotics; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C585498:Cyp1b1 protein, mouse; C585499:Cyp1b1 protein, rat; D065633:Cytochrome P-450 CYP1B1; C122107:microsomal glutathione S-transferase-I; D005982:Glutathione Transferase
keywords: endothelial homeostasis; gene regulation; hemodynamics; nuclear hormone receptor