Vascular COX-2 Modulates Blood Pressure and Thrombosis in Mice
Yu, Ying; Ricciotti, Emanuela; Scalia, Rosario; Tang, Soon Yew; Grant, Gregory; Yu, Zhou; Landesberg, Gavin; Crichton, Irene; Wu, Weichen; Pure, Ellen; Funk, Colin D.; FitzGerald, Garret A.
2012
Source PublicationSCIENCE TRANSLATIONAL MEDICINE
ISSN1946-6234
Volume4Issue:132
Status已发表
DOI10.1126/scitranslmed.3003787
Abstract

Prostacyclin (PGI(2)) is a vasodilator and platelet inhibitor, properties consistent with cardioprotection. More than a decade ago, inhibition of cyclooxygenase-2 (COX-2) by the nonsteroidal anti-inflammatory drugs (NSAIDs) rofecoxib and celecoxib was found to reduce the amount of the major metabolite of PGI(2) (PGI-M) in the urine of healthy volunteers. This suggested that NSAIDs might cause adverse cardiovascular events by reducing production of cardioprotective PGI(2). This prediction was based on the assumption that the concentration of PGI-M in urine likely reflected vascular production of PGI(2) and that other cardioprotective mediators, especially nitric oxide (NO), were not able to compensate for the loss of PGI(2). Subsequently, eight placebo-controlled clinical trials showed that NSAIDs that block COX-2 increase adverse cardiovascular events. We connect tissue-specific effects of NSAID action and functional correlates in mice with clinical outcomes in humans by showing that deletion of COX-2 in the mouse vasculature reduces excretion of PGI-M in urine and predisposes the animals to both hypertension and thrombosis. Furthermore, vascular disruption of COX-2 depressed expression of endothelial NO synthase and the consequent release and function of NO. Thus, suppression of PGI(2) formation resulting from deletion of vascular COX-2 is sufficient to explain the cardiovascular hazard from NSAIDs, which is likely to be augmented by secondary mechanisms such as suppression of NO production.

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WOS Research AreaCell Biology ; Research & Experimental Medicine
WOS SubjectCell Biology ; Medicine, Research & Experimental
WOS IDWOS:000303596400008
WOS KeywordNONSTEROIDAL ANTIINFLAMMATORY DRUGS ; TRANSGENIC MICE ; NITRIC-OXIDE ; PROSTACYCLIN ; CYCLOOXYGENASE-2 ; INHIBITION ; RISK ; RECEPTOR ; SYSTEM ; CELLS
Original Document TypeArticle
Citation statistics
Cited Times:140[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttps://kms.shanghaitech.edu.cn/handle/2MSLDSTB/120765
Collection个人在本单位外知识产出
Corresponding AuthorYu, Ying; FitzGerald, Garret A.
Affiliation1.Univ Penn, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA
2.Temple Univ, Dept Physiol, Philadelphia, PA 19140 USA
3.Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA
4.Queens Univ, Dept Biomed & Mol Sci, Kingston, ON K7L 3N6, Canada
Recommended Citation
GB/T 7714
Yu, Ying,Ricciotti, Emanuela,Scalia, Rosario,et al. Vascular COX-2 Modulates Blood Pressure and Thrombosis in Mice[J]. SCIENCE TRANSLATIONAL MEDICINE,2012,4(132).
APA Yu, Ying.,Ricciotti, Emanuela.,Scalia, Rosario.,Tang, Soon Yew.,Grant, Gregory.,...&FitzGerald, Garret A..(2012).Vascular COX-2 Modulates Blood Pressure and Thrombosis in Mice.SCIENCE TRANSLATIONAL MEDICINE,4(132).
MLA Yu, Ying,et al."Vascular COX-2 Modulates Blood Pressure and Thrombosis in Mice".SCIENCE TRANSLATIONAL MEDICINE 4.132(2012).
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