Cyclooxygenases, microsomal prostaglandin E synthase-1, and cardiovascular function.
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 antiinflammatory efficacy by depressing PGE(2), while avoiding the adverse cardiovascular consequences associated with PGHS-2-mediated PGI(2) suppression.
Cheng
Yan
Y
Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Wang
Miao
M
Yu
Ying
Y
Lawson
John
J
Funk
Colin D
CD
Fitzgerald
Garret A
GA
D000818:Animals; D001794:Blood Pressure; D002319:Cardiovascular System / Q000276:immunology / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000502:physiology*; D015232:Dinoprostone / Q000378:metabolism; D011464:Epoprostenol / Q000378:metabolism; D005260:Female; D019746:Intramolecular Oxidoreductases / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071876:Prostaglandin-E Synthases; D013931:Thromboxanes
D013931:Thromboxanes; D011464:Epoprostenol; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone