Microsomal prostaglandin E synthase-1 inhibition in cardiovascular inflammatory disease

Journal of Internal Medicine
Miao WangGarret A Fitzgerald

Abstract

Prostaglandins (PGs), particularly PGE2 and prostacyclin (PGI2), are potent mediators of pain and inflammation. Both atherosclerosis and aortic aneurysm exhibit the hallmarks of inflammation. However, randomized trials of inhibitors of PG synthesis--nonsteroidal anti-inflammatory drugs--reveal that they predispose to cardiovascular risk. This appears to be consequent to inhibition of PGI2 and PGE2 formed by cyclooxygenase-2 (COX-2). Inhibitors of microsomal PGE synthase-1 (mPGES-1) are being developed for relief of pain and interest has focused on their potential impact on the cardiovascular system. Deletion of mPGES-1 retards atherogenesis and limits aortic aneurysm formation in hyperlipidaemic mice. However, it does not predispose to thrombogenesis and has a limited impact on blood pressure compared to inhibition of COX-2. This occurs despite the potential of the suppressed PGE2 in affording cardioprotection via its EP2 and EP4 receptors. However, deletion of mPGES-1 permits rediversion of the PGH2 substrate to other PG synthases and augmented formation of PGI2 and PGD2 mitigates this effect. However, increased PGI2 may also attenuate relief of pain. Pain relief seems likely to be a nuanced indication for mPGES-1 inhibitors, ...Continue Reading

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