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学科主题基础医学
Metabolic profiling of murine plasma reveals an unexpected biomarker in rofecoxib-mediated cardiovascular events
Liu, Jun-Yan1,2; Li, Ning3; Yang, Jun1,2; Li, Nan4; Qiu, Hong3; Ai, Ding1,2,4; Chiamvimonvat, Nipavan3; Zhu, Yi4; Hammock, Bruce D.1,2
关键词cardiovascular side effect coxib eicosanoids metabolomics Vioxx
刊名PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2010-09-28
DOI10.1073/pnas.1011278107
107期:39页:17017-17022
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Multidisciplinary Sciences
资助者National Institute of Environmental Health Sciences ; National Heart, Lung, and Blood Institute ; Major National Basic Research Grant of China ; Cystic Fibrosis Foundation, Inc. ; Veterans Affairs ; American Heart Association ; National Institute of Environmental Health Sciences ; National Heart, Lung, and Blood Institute ; Major National Basic Research Grant of China ; Cystic Fibrosis Foundation, Inc. ; Veterans Affairs ; American Heart Association
研究领域[WOS]Science & Technology - Other Topics
关键词[WOS]NONSTEROIDAL ANTIINFLAMMATORY DRUGS ; ENDOTHELIUM-DEPENDENT VASOCONSTRICTOR ; INCREASED PLATELET AGGREGABILITY ; EPOXIDE HYDROLASE INHIBITORS ; ACUTE MYOCARDIAL-INFARCTION ; CORONARY HEART-DISEASE ; 20-HYDROXYEICOSATETRAENOIC ACID ; 20-HETE CONTRIBUTES ; RISK ; TOXICITY
英文摘要

Chronic administration of high levels of selective COX-2 inhibitors (coxibs), particularly rofecoxib, valdecoxib, and parecoxib, increases risk for cardiovascular disease. Understanding the possibly multiple mechanisms underlying these adverse cardiovascular events is critical for evaluating the risks and benefits of coxibs and for development of safer coxibs. The current understanding of these mechanisms is likely incomplete. Using a metabolomics approach, we demonstrate that oral administration of rofecoxib for 3 mo results in a greater than 120-fold higher blood level of 20-hydroxyeicosatetraenoic acid (20-HETE), which correlates with a significantly shorter tail bleeding time in a murine model. We tested the hypothesis that this dramatic increase in 20-HETE is attributable to inhibition of its metabolism and that the shortened bleeding time following rofecoxib administration is attributable, in part, to this increase. The s.c. infusion of 20-HETE shortened the tail bleeding time dramatically. Neither 20-HETE biosynthesis nor cytochrome P4A-like immune reactivity was increased by rofecoxib administration, but 20-HETE production increased in vitro with the addition of coxib. 20-HETE is significantly more potent than its COX-mediated metabolites in shortening clotting time in vitro. Furthermore, 20-HETE but not rofecoxib significantly increases rat platelet aggregation in vitro in a dose-dependent manner. These data suggest 20-HETE as a marker of rofecoxib exposure and that inhibition of 20-HETE′s degradation by rofecoxib is a partial explanation for its dramatic increase, the shortened bleeding time, and, possibly, the adverse cardiovascular events associated with rofecoxib.

语种英语
所属项目编号ES02710 ; P42 ES04699 ; HL85727 ; HL85844 ; 2010CB912504
资助者National Institute of Environmental Health Sciences ; National Heart, Lung, and Blood Institute ; Major National Basic Research Grant of China ; Cystic Fibrosis Foundation, Inc. ; Veterans Affairs ; American Heart Association ; National Institute of Environmental Health Sciences ; National Heart, Lung, and Blood Institute ; Major National Basic Research Grant of China ; Cystic Fibrosis Foundation, Inc. ; Veterans Affairs ; American Heart Association
WOS记录号WOS:000282211700052
Citation statistics
Cited Times:77[WOS]   [WOS Record]     [Related Records in WOS]
文献类型期刊论文
版本出版稿
条目标识符http://ir.bjmu.edu.cn/handle/400002259/55287
Collection北京大学基础医学院_生理学与病理生理学系
作者单位1.Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA
2.Univ Calif Davis, Univ Calif Davis Canc Ctr, Davis, CA 95616 USA
3.Univ Calif Davis, Div Cardiovasc Med, Davis, CA 95616 USA
4.Beijing Univ, Dept Physiol, Beijing 100083, Peoples R China
Recommended Citation
GB/T 7714
Liu, Jun-Yan,Li, Ning,Yang, Jun,et al. Metabolic profiling of murine plasma reveals an unexpected biomarker in rofecoxib-mediated cardiovascular events[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2010,107(39):17017-17022.
APA Liu, Jun-Yan.,Li, Ning.,Yang, Jun.,Li, Nan.,Qiu, Hong.,...&Hammock, Bruce D..(2010).Metabolic profiling of murine plasma reveals an unexpected biomarker in rofecoxib-mediated cardiovascular events.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,107(39),17017-17022.
MLA Liu, Jun-Yan,et al."Metabolic profiling of murine plasma reveals an unexpected biomarker in rofecoxib-mediated cardiovascular events".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 107.39(2010):17017-17022.
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