Cardiovascular Consequences of Prostanoid I Receptor Deletion in Microsomal Prostaglandin E Synthase-1–Deficient Hyperlipidemic Mice. Issue 4 (26th July 2016)

• Record Type: Journal Article
• Authors: Tang, Soon Yew; Monslow, James; R. Grant, Gregory; Todd, Leslie; Pawelzik, Sven-Christian; Chen, Lihong; Lawson, John; Puré, Ellen; FitzGerald, Garret A.
• Is Part Of: Circulation. Volume 134:Issue 4(2016)
• Publication Date: 2016-07-26
• Subjects: atherosclerosis -- cyclooxygenase 2 -- dinoprostone -- epoprostenol -- prostaglandin-E synthase -- thrombosis; Blood -- Circulation -- Periodicals; Cardiovascular system -- Periodicals; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; 616.1
• DOI: 10.1161/CIRCULATIONAHA.116.022308
• Languages: English
• ISSNs: 0009-7322

Abstract

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. Abstract : Supplemental Digital Content is available in the text.