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学科主题: 基础医学
题名:
Shear stress activation of nuclear receptor PXR in endothelial detoxification
作者: Wang, Xiaohong1,2,3,4,5; Fang, Xi1,2; Zhou, Jing3,4,5; Chen, Zhen3,4,5; Zhao, Beilei1,2; Xiao, Lei6; Liu, Ao1,2; Li, Yi-Shuan J.3,4,5; Shyy, John Y. -J.3,4,5,6; Guan, Youfei1,2; Chien, Shu3,4,5; Wang, Nanping1,2,6
关键词: hemodynamics ; endothelial homeostasis ; nuclear hormone receptor ; gene regulation
刊名: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
发表日期: 2013-08-06
DOI: 10.1073/pnas.1312065110
卷: 110, 期:32, 页:13174-13179
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Multidisciplinary Sciences
研究领域[WOS]: Science & Technology - Other Topics
关键词[WOS]: PREGNANE-X-RECEPTOR ; REGULATES DRUG-METABOLISM ; NITRIC-OXIDE SYNTHASE ; RESPONSE ELEMENT ; P-GLYCOPROTEIN ; CELL APOPTOSIS ; IN-VITRO ; EXPRESSION ; INDUCTION ; FLOW
英文摘要:

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-alpha 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.

语种: 英语
所属项目编号: 30890041 ; 81220108005 ; 2010CB912500 ; HL108735-01A1
项目资助者: National Science Foundation of China ; Ministry of Science and Technology of China ; National Institutes of Health
WOS记录号: WOS:000322771100074
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/58978
Appears in Collections:基础医学院_心血管所_期刊论文

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作者单位: 1.Peking Univ, Inst Cardiovasc Sci, Beijing 100191, Peoples R China
2.Peking Univ, Minist Educ, Key Lab Mol Cardiol, Beijing 100191, Peoples R China
3.Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA
4.Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA
5.Univ Calif San Diego, Inst Engn Med, La Jolla, CA 92093 USA
6.Xi An Jiao Tong Univ, Cardiovasc Res Ctr, Xian 710061, Peoples R China

Recommended Citation:
Wang, Xiaohong,Fang, Xi,Zhou, Jing,et al. Shear stress activation of nuclear receptor PXR in endothelial detoxification[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2013,110(32):13174-13179.
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