Format

Send to

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

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

Author information

1
From Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, Department of Systems Pharmacology and Translational Therapeutics (S.Y.T., J.M., L.T., S.-C.P., L.C., E.P., G.A.F.); Department of Animal Biology, School of Veterinary Medicine (S.Y.T., G.R.G., J.L.); and Department of Genetics, University of Pennsylvania, Philadelphia (J.M.).
2
From Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, Department of Systems Pharmacology and Translational Therapeutics (S.Y.T., J.M., L.T., S.-C.P., L.C., E.P., G.A.F.); Department of Animal Biology, School of Veterinary Medicine (S.Y.T., G.R.G., J.L.); and Department of Genetics, University of Pennsylvania, Philadelphia (J.M.). garret@upenn.edu.

Abstract

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

PMID:
27440004
PMCID:
PMC4963279
DOI:
10.1161/CIRCULATIONAHA.116.022308
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center