Cardiovascular Consequences of Prostanoid I Receptor Deletion in Microsomal Prostaglandin E Synthase-1-Deficient Hyperlipidemic Mice

Circulation. 2016 Jul 26;134(4):328-38. doi: 10.1161/CIRCULATIONAHA.116.022308.


Background: Inhibitors of cyclooxygenase-2 alleviate pain and reduce fever and inflammation by suppressing the biosynthesis of prostacyclin (PGI2) and prostaglandin E2. However, suppression of these prostaglandins, particularly PGI2, by cyclooxygenase-2 inhibition or deletion of its I prostanoid receptor also predisposes to accelerated atherogenesis and thrombosis in mice. By contrast, deletion of microsomal prostaglandin E synthase 1 (mPGES-1) confers analgesia, attenuates atherogenesis, and fails to accelerate thrombogenesis, while suppressing prostaglandin E2, but increasing biosynthesis of PGI2.

Methods: To address the cardioprotective contribution of PGI2, we generated mice lacking the I prostanoid receptor together with mPges-1 on a hyperlipidemic background (low-density lipoprotein receptor knockouts).

Results: mPges-1 depletion modestly increased thrombogenesis, but this response was markedly further augmented by coincident deletion of the I prostanoid receptor (n=10-18). By contrast, deletion of the I prostanoid receptor had no effect on the attenuation of atherogenesis by mPGES-1 deletion in the low-density lipoprotein receptor knockout mice (n=17-21).

Conclusions: Although suppression of prostaglandin E2 accounts for the protective effect of mPGES-1 deletion in atherosclerosis, augmentation of PGI2 is the dominant contributor to its favorable thrombogenic profile. The divergent effects on these prostaglandins suggest that inhibitors of mPGES-1 may be less likely to cause cardiovascular adverse effects than nonsteroidal anti-inflammatory drugs specific for inhibition of cyclooxygenase-2.

Keywords: atherosclerosis; cyclooxygenase 2; dinoprostone; epoprostenol; prostaglandin-E synthase; thrombosis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Aortic Diseases / enzymology
  • Aortic Diseases / genetics
  • Atherosclerosis / enzymology*
  • Atherosclerosis / genetics
  • Carotid Artery, Common / radiation effects
  • Carotid Stenosis / etiology
  • Epoprostenol / physiology*
  • Hyperlipidemias / enzymology
  • Hyperlipidemias / genetics*
  • Lasers / adverse effects
  • Mice
  • Mice, Knockout
  • Microsomes / enzymology
  • Polymorphism, Single Nucleotide
  • Prostaglandin-E Synthases / deficiency*
  • Prostaglandin-E Synthases / genetics
  • Prostaglandin-E Synthases / physiology
  • Receptors, Epoprostenol
  • Receptors, LDL / deficiency
  • Receptors, LDL / genetics
  • Receptors, Prostaglandin / deficiency*
  • Receptors, Prostaglandin / genetics
  • Receptors, Prostaglandin / physiology


  • Ptgir protein, mouse
  • Receptors, Epoprostenol
  • Receptors, LDL
  • Receptors, Prostaglandin
  • Epoprostenol
  • Prostaglandin-E Synthases