Lipoprotein-Associated and Secreted Phospholipases A 2 in Cardiovascular Disease

Abstract

Phospholipases A2 (PLA2s) belong to a superfamily of enzymes that catalyze the hydrolysis of glycerophospholipids at the sn-2 position, producing nonesterified fatty acids, such as arachidonic acid, and lysophospholipids.1,2 In many cases, the PLA2 lipid products lead to the generation of a variety of downstream signaling molecules, including prostaglandins, leukotrienes, lysophospholipids, platelet-activating factor (PAF), and oxidized lipids, that induce a multitude of biological actions in virtually all tissues, including the cardiovascular system.3,–,8 PLA2s comprise distinct sets of enzymes with different localizations: 1 cytosolic enzymes that are Ca2+-dependent (cPLA2), Ca2+-independent (iPLA2), or specific for PAF (intracellular PAF-acetylhydrolase); and 2 extracellular enzymes, either associated with lipoproteins (Lp-PLA2, also known as the secreted PAF acetylhydrolase) or typically secreted (sPLA2) and present in the extracellular space. The cPLA2 family consists of 6 enzymes, among which the cytosolic Ca2+-dependent cPLA2α (85 kDa, group IVA) plays a major role in the initiation of arachidonic acid metabolism from cell membrane phospholipids.9 The iPLA2 or patatin-like phospholipase domain–containing (PNPLA) family contains 9 enzymes, some of which work as phospholipases and others as lipases, with the Ca2+-independent iPLA2-β (88 to 90 kDa, group VIA-2) being one of the best-studied members.8,10 Lp-PLA2 exhibits unique substrate specificity toward PAF and oxidized phospholipids (oxPLs).11 The sPLA2 family consists of 10 isozymes with low molecular mass that are involved in a number of biological processes, including eicosanoid generation, inflammation, and host defense against bacterial infection.12 Arterial inflammation plays a central role in the pathogenesis of atherosclerosis and adverse cardiovascular events. Although cPLA2-α and iPLA2-β are likely to contribute …