COX-2 inhibitors are believed to exert both their beneficial and their adverse effects by suppression of COX-2-derived prostacyclin (PGI2) and prostaglandin E2 (PGE2). These substances help prevent platelet clumping in blood vessels and vessel relaxation and/or constriction, respectively. Therefore, the challenge has been to identify a mechanism whereby PGI2 and PGE2 expression can be suppressed while avoiding adverse cardiovascular events. FitzGerald and colleagues now show that selective inhibition, knockout, or mutation of COX-2, or deletion of the receptor for COX-2-derived PGI2, accelerates the formation of blood clots and elevates blood pressure in mice. These responses were attenuated by COX-1 knock down, which mimics the beneficial effects of low-dose aspirin.
PGE2 biosynthesis is catalyzed by the coordinate actions of COX enzymes and microsomal PGE synthase-1 (mPGES-1). In the effort to propose an alternative therapeutic option to COX-2 inhibitors, FitzGerald et al. showed that deletion of mPGES-1 suppressed PGE2 expression, augmented PGI2 expression, but most importantly, affected neither blood clotting nor blood pressure. These results suggest that inhibitors of mPGES-1 may offer anti-inflammatory efficacy by depressing PGE2, while avoiding the adverse cardiovascular consequences associated with COX-2-mediated PGI2 suppression.
TITLE: Cyclooxygenases, microsomal prostaglandin E synthase-1, and cardiovascular function
Garret A. FitzGerald
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
Phone: (215) 898-1184; Fax: (215) 573-9135; E-mail: firstname.lastname@example.org
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