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

J Clin Invest. 2006 May;116(5):1391-9. doi: 10.1172/JCI27540. Epub 2006 Apr 13.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Pressure
  • Cardiovascular System / immunology
  • Cardiovascular System / pathology*
  • Cyclooxygenase 2 / genetics*
  • Cyclooxygenase 2 / physiology*
  • Dinoprostone / metabolism
  • Epoprostenol / metabolism
  • Female
  • Intramolecular Oxidoreductases / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Prostaglandin-E Synthases
  • Thromboxanes


  • Thromboxanes
  • Epoprostenol
  • Cyclooxygenase 2
  • Intramolecular Oxidoreductases
  • Prostaglandin-E Synthases
  • Ptges protein, mouse
  • Dinoprostone