Recent Developments with Lipoprotein-Associated Phospholipase A2 Inhibitors

Abstract

Lipoprotein-associated phospholipase A₂ (Lp-PLA₂) is a calcium-independent phospholipase A₂ enzyme secreted by leukocytes and associated with circulating low-density lipoprotein and macrophages in atherosclerotic plaques. Until recently, the biological role of Lp-PLA₂ in atherosclerosis was controversial, but now the preponderance of evidence demonstrates a proatherogenic role of this enzyme. Lp-PLA₂ generates two proinflammatory mediators, lysophosphatidylcholine and oxidized nonesterified fatty acids, which play a major role in the development of atherosclerotic lesions and formation of a necrotic core, leading to more vulnerable plaques. These findings have opened the door to a potential novel therapeutic target, selective inhibition of Lp-LPA₂. Recently, both animal models and human studies have shown that selective inhibition of Lp-PLA₂ reduces plasma Lp-PLA₂ activity, plaque area, and necrotic core area. This article reviews the most recent developments with Lp-PLA₂ inhibitors.