Cyclooxygenase-1, not cyclooxygenase-2, is responsible for physiological production of prostacyclin in the cardiovascular system

被引：104

作者：

Kirkby, Nicholas S. ^{[1
,2
]}

Lundberg, Martina H. ^{[1
,2
]}

Harrington, Louise S. ^{[1
]}

Leadbeater, Philip D. M. ^{[1
]}

Milne, Ginger L. ^{[3
,4
]}

Potter, Claire M. F. ^{[1
]}

Al-Yamani, Malak ^{[1
,5
]}

Adeyemi, Oladipupo ^{[1
]}

Warner, Timothy D. ^{[2
]}

Mitchell, Jane A. ^{[1
,6
]}

机构：

[1] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London SW3 6LY, England

[2] Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London EC1M 6BQ, England

[3] Vanderbilt Univ, Dept Pharmacol, Nashville, TN 37232 USA

[4] Vanderbilt Univ, Dept Med, Nashville, TN 37232 USA

[5] King Saud Univ, King Fahad Cardiac Ctr, Riyadh 11472, Saudi Arabia

[6] Inst Cardiovasc Med ICMS, London SW3 6NP, England

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2012年 / 109卷 / 43期

基金：

美国国家卫生研究院; 英国惠康基金;

关键词：

nonsteroidal anti-inflammatory drugs; thrombosis; COX-2 selective drugs; rofecoxib; NITRIC-OXIDE SYNTHASE; SHEAR-STRESS; PROSTAGLANDIN SYNTHASE; ANTIINFLAMMATORY DRUGS; VASCULAR ENDOTHELIUM; GENE-EXPRESSION; MESSENGER-RNA; COX ISOFORMS; INHIBITION; DISRUPTION;

D O I：

10.1073/pnas.1209192109

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Prostacyclin is an antithrombotic hormone produced by the endothelium, whose production is dependent on cyclooxygenase (COX) enzymes of which two isoforms exist. It is widely believed that COX-2 drives prostacyclin production and that this explains the cardiovascular toxicity associated with COX-2 inhibition, yet the evidence for this relies on indirect evidence from urinary metabolites. Here we have used a range of experimental approaches to explore which isoform drives the production of prostacyclin in vitro and in vivo. Our data show unequivocally that under physiological conditions it is COX-1 and not COX-2 that drives prostacyclin production in the cardiovascular system, and that urinary metabolites do not reflect prostacyclin production in the systemic circulation. With the idea that COX-2 in endothelium drives prostacyclin production in healthy individuals removed, we must seek new answers to why COX-2 inhibitors increase the risk of cardiovascular events to move forward with drug discovery and to enable more informed prescribing advice.

引用

页码：17597 / 17602

页数：6

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