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Cardiovascular Consequences of Prostanoid I Receptor Deletion in Microsomal Prostaglandin E Synthase-1-Deficient Hyperlipidemic Mice.
- Source :
-
Circulation [Circulation] 2016 Jul 26; Vol. 134 (4), pp. 328-38. - Publication Year :
- 2016
-
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.<br />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).<br />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).<br />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.<br /> (© 2016 American Heart Association, Inc.)
- Subjects :
- Animals
Aortic Diseases enzymology
Aortic Diseases genetics
Atherosclerosis genetics
Carotid Artery, Common radiation effects
Carotid Stenosis etiology
Hyperlipidemias enzymology
Lasers adverse effects
Mice
Mice, Knockout
Microsomes enzymology
Polymorphism, Single Nucleotide
Prostaglandin-E Synthases genetics
Prostaglandin-E Synthases physiology
Receptors, Epoprostenol
Receptors, LDL deficiency
Receptors, LDL genetics
Receptors, Prostaglandin genetics
Receptors, Prostaglandin physiology
Atherosclerosis enzymology
Epoprostenol physiology
Hyperlipidemias genetics
Prostaglandin-E Synthases deficiency
Receptors, Prostaglandin deficiency
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4539
- Volume :
- 134
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Circulation
- Publication Type :
- Academic Journal
- Accession number :
- 27440004
- Full Text :
- https://doi.org/10.1161/CIRCULATIONAHA.116.022308