Cardiovascular Consequences of Prostanoid I Receptor Deletion in Microsomal Prostaglandin E Synthase-1 Deficient Hyperlipidemic Mice
Background—Inhibitors of cyclooxygenase-2 (COX-2) alleviate pain and reduce fever and inflammation by suppressing biosynthesis of prostacyclin (PGI2) and prostaglandin E2 (PGE2). However, suppression of these PGs, particularly PGI2, by COX-2 inhibition or deletion of its I prostanoid (Ip) 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 PGE2, but increasing biosynthesis of PGI2.
Methods—To address the cardioprotective contribution of PGI2, we generated mice lacking the I prostanoid (Ip) receptor together with mPges-1 on a hyperlipidemic background (LdlR KOs).
Results—mPges-1 depletion modestly increased thrombogenesis, but this response was markedly further augmented by coincident deletion of the Ip (n= 10-18). By contrast, deletion of the Ip had no effect on the attenuation of atherogenesis by mPGES-1 deletion in the LdlR KOs (n= 17-21).
Conclusions—While suppression of PGE2 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 PGs suggest that inhibitors of mPGES-1 may be less likely to cause cardiovascular adverse effects than NSAIDs specific for inhibition of COX-2.
- Received December 9, 2015.
- Revision received May 9, 2016.
- Accepted June 2, 2016.