Cyclooxygenases, microsomal prostaglandin E synthase-1, and cardiovascular function

被引:294
作者
Cheng, Y
Wang, M
Yu, Y
Lawson, J
Funk, CD
FitzGerald, GA
机构
[1] Univ Penn, Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA
[2] Queens Univ, Dept Physiol, Kingston, ON K7L 3N6, Canada
[3] Queens Univ, Dept Biochem, Kingston, ON K7L 3N6, Canada
关键词
D O I
10.1172/JCI27540
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
We investigated the mechanisms by which inhibitors of prostaglandin G/H synthase-2 (PGHS-2; known colloquially as COX-2) increase the incidence of myocardial infarction and stroke. These inhibitors are believed to exert both their beneficial and their adverse effects by suppression of PGHS-2-derived prostacyclin (PGI(2)) and PGE(2). Therefore, the challenge remains to identify a mechanism whereby PGI(2) and PGE(2) expression can be suppressed while avoiding adverse cardiovascular events. Here, selective inhibition, knockout, or mutation of PGHS-2, or deletion of the receptor for PGHS-2-derived PGI(2), was shown to accelerate thrombogenesis and elevate blood pressure in mice. These responses were attenuated by COX-1 knock down, which mimics the beneficial effects of low-dose aspirin. PGE(2) biosynthesis is catalyzed by the coordinate actions of COX enzymes and microsomal PGE synthase-1 (mPGES-1). We show that deletion of mPGES-1 depressed PGE(2) expression, augmented PGI(2) expression, and had no effect on thromboxane biosynthesis in vivo. Most importantly, mPGES-1 deletion affected neither thrombogenesis nor blood pressure. These results suggest that inhibitors of mPGES-1 may retain their andinflammatory efficacy by depressing PGE(2), while avoiding the adverse cardiovascular consequences associated with PGHS-2-mediated PGI(2) suppression.
引用
收藏
页码:1391 / 1399
页数:9
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