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

Article

关键词: BLOOD-PRESSURE;    E SYNTHASE;    DEFICIENT MICE;    MURINE MODELS;    DRUG TARGET;    PROSTACYCLIN;    ATHEROSCLEROSIS;    LACKING;    COX-2;    ATHEROGENESIS;   

DOI  :  10.1161/CIRCULATIONAHA.116.022308

来源: SCIE

【 摘 要 】

BACKGROUND: Inhibitors of cyclooxygenase-2 alleviate pain and reduce fever and inflammation by suppressing the biosynthesis of prostacyclin (PGI(2)) and prostaglandin E-2. However, suppression of these prostaglandins, particularly PGI(2), 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 E-2, but increasing biosynthesis of PGI(2). METHODS: To address the cardioprotective contribution of PGI(2), 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 E-2 accounts for the protective effect of mPGES-1 deletion in atherosclerosis, augmentation of PGI(2) 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.

【 授权许可】

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