Phospholipase A ₂ in Vascular Disease

Abstract

Abstract-Secretory phospholipase A 2 (PLA 2 ) can be proatherogenic both in the circulation and in the arterial wall. In blood plasma, PLA 2 can modify the circulating lipoproteins and so induce formation of small dense LDL particles, which are associated with increased risk for cardiovascular disease. In the arterial wall, PLA 2 can hydrolyze lipoproteins. The PLA 2 -modified lipoproteins bind tightly to extracellular proteoglycans, which may lead to their enhanced retention in the arterial wall. The modified lipoproteins may also aggregate and fuse, which can lead to accumulation of their lipids within the extracellular matrix. The PLA 2 -modified particles are more susceptible to further modifications by other enzymes and agents and can be taken up by macrophages, leading to accumulation of intracellular lipids. In addition, lysophospholipids and free fatty acids, the hydrolysis products of PLA 2 , promote atherogenesis. Thus, these lipid mediators can be carried, either by the PLA 2 -modified lipoproteins themselves or by albumin, into the arterial cells, which then undergo functional alterations. This may, in turn, lead to specific changes in the extracellular matrix, which increase the retention and accumulation of lipoproteins within the matrix. In the present article, we discuss the possible actions of PLA 2 enzymes, especially PLA 2 -IIA, in the arterial wall during atherogenesis. (Circ Res. 2001;89:298-304.)

Transgenic Expression of Group V, but Not Group X, Secreted Phospholipase A2 in Mice Leads to Neonatal Lethality because of Lung Dysfunction

“…C57BL/6 and 129/Sv)) show marked resistance to bacterial infection (19,20), thus substantiating the in vitro observations that this enzyme efficiently hydrolyzes bacterial membranes (21). In addition, sPLA 2 -IIA Tg mice show increased lipoprotein hydrolysis and atherosclerosis (22)(23)(24), although sPLA 2 -V and sPLA 2 -X have also been implicated in these processes (25,26). Mouse strains intrinsically deficient in sPLA 2 -IIA because of a frameshift mutation in its gene are susceptible to intestinal tumorigenesis (45).…”

“…Because of the secreted moiety of sPLA 2 s, it is likely that their target substrates also exist in the extracellular milieu. In fact, several sPLA 2 s hydrolyze phospholipids in bacterial membranes (19 -21), plasma lipoproteins (22)(23)(24)(25)(26), lung surfactant (27)(28)(29)(30)(31)(32)(33)(34)(35), and so on with distinct poten-cies in vitro, suggesting that they play divergent roles in various biological events. However, the proposed roles of sPLA 2 enzymes have largely been inferred from their enzymatic and biochemical properties, the effects of their overexpression or exogenous addition in in vitro experimental settings, or the use of pharmacological inhibitors (whose specificity may not be strictly defined).…”

Cysteine Protease Cathepsin F Is Expressed in Human Atherosclerotic Lesions, Is Secreted by Cultured Macrophages, and Modifies Low Density Lipoprotein Particles in Vitro

“…De Vries et al (68) have shown that monocyte-derived macrophages can lower their environmental pH to as low as 5.5 in the presence of oxidized LDL, a pH condition optimal for most cathepsins including cathepsin F. Interestingly, the acidification of the pericellular environment of macrophages is frequently coupled with the secretion of several cathepsins (23). Furthermore, lipolytic modifications of lipoproteins in the arterial intima, by producing free fatty acids, may also participate in the generation of an acidic microenvironment (69), and finally, the negatively charged glycosaminoglycan chains of proteoglycans may decrease the pH locally by attracting positively charged hydrogen ions (46).…”

Group IB Secretory Phospholipase A2 Promotes Matrix Metalloproteinase-2-mediated Cell Migration via the Phosphatidylinositol 3-Kinase and Akt Pathway

“…Arachidonic acid is the key substrate for the synthesis of potent lipid mediators of inflammation. Several mammalian secretory PLA 2 s (sPLA 2 s) have been characterized and classified into different families (11). At present, 12 distinct sPLA 2 s have been identified in mammals and classified into different groups, depending on their primary structures as characterized by the number and position of cysteine residues.…”