The deposition of cholesterol ester within foam cells of the artery wall is fundamental to the pathogenesis of atherosclerosis. Modifications of low density lipoprotein (LDL), such as oxidation, are prerequisite events for the formation of foam cells. We demonstrate here that group X secretory phospholipase A 2 (sPLA 2 -X) may be involved in this process. sPLA 2 -X was found to induce potent hydrolysis of phosphatidylcholine in LDL leading to the production of large amounts of unsaturated fatty acids and lysophosphatidylcholine (lyso-PC), which contrasted with little, if any, lipolytic modification of LDL by the classic types of group IB and IIA secretory PLA 2 s. Treatment with sPLA 2 -X caused an increase in the negative charge of LDL with little modification of apolipoprotein B (apoB) in contrast to the excessive aggregation and fragmentation of apoB in oxidized LDL. The sPLA 2 -X-modified LDL was efficiently incorporated into macrophages to induce the accumulation of cellular cholesterol ester and the formation of non-membrane-bound lipid droplets in the cytoplasm, whereas the extensive accumulation of multilayered structures was found in the cytoplasm in oxidized LDL-treated macrophages. Immunohistochemical analysis revealed marked expression of sPLA 2 -X in foam cell lesions in the arterial intima of high fat-fed apolipoprotein E-deficient mice. These findings suggest that modification of LDL by sPLA 2 -X in the arterial vessels is one of the mechanisms responsible for the generation of atherogenic lipoprotein particles as well as the production of various lipid mediators, including unsaturated fatty acids and lyso-PC.Initiation of atherosclerosis is characterized by the appearance of fatty streaks underlying the endothelium of large arteries. Recruitment of macrophages and their subsequent uptake of low density lipoprotein (LDL) 1 -derived cholesterol are the major cellular events contributing to fatty streak formation (1, 2). Oxidative modifications in the lipid and apolipoprotein B (apoB) components of LDL are thought to drive the formation of fatty streaks (2, 3), because oxidized LDL can be incorporated into the macrophages via scavenger receptors leading to the formation of foam cells that contain massive amounts of cholesterol esters. In addition, there is substantial evidence that LDL oxidation occurs in both animals and humans during the progression of atherogenesis (4). However, prospective clinical trials with antioxidants, such as vitamin E and beta carotene, in patients with pre-existing atherosclerosis, have thus far been disappointing (5). These findings suggest that other types of LDL modifications, such as that resulting from lipolytic enzymes (6), also play pivotal roles in the formation of foam cells.Phospholipase A 2 (PLA 2 ) are a diverse family of lipolytic enzymes that hydrolyze the sn-2 fatty acid ester bond of glycerophospholipids to produce free fatty acids and lysophospholipids (7,8). Over the past two decades, a number of PLA 2 s have been identified and classified into differen...

The quantitative or qualitative decline of high-density lipoprotein (HDL) is linked to the pathogenesis of atherosclerosis because of its antiatherogenic functions, including the mediation of reverse cholesterol transport from the peripheral cells to the liver. We have recently shown that group X secretory phospholipase A(2) (sPLA(2)-X) is involved in the pathogenesis of atherosclerosis via potent lipolysis of low-density lipoprotein (LDL) leading to macrophage foam cell formation. We demonstrate here that sPLA(2)-X as well as group V secretory PLA(2) (sPLA(2)-V), another group of sPLA(2) that can potently hydrolyze phosphatidylcholine (PC), also possess potent hydrolytic potency for PC in HDL linked to the production of a large amount of unsaturated fatty acids and lysophosphatidylcholine (lysoPC). In contrast, the classical types of group IB and IIA secretory PLA(2)s evoked little, if any, lypolytic modification of HDL. Treatment with sPLA(2)-X or -V also caused an increase in the negative charge of HDL with no oxidation and little modification of apolipoprotein AI (apoAI). Modification with sPLA(2)-X or -V resulted in significant decrease in the capacity of HDL to cause cellular cholesterol efflux from lipid-loaded macrophages. Immunohistochemical analysis revealed significant expression of sPLA(2)-X in foam cell lesions in the arterial intima of Watanabe heritable hyperlipidemic (WHHL) rabbit. These findings suggest that lipolytic modification of HDL by sPLA(2)-X or -V causes drastic change of HDL in terms of the production of a large amount of unsaturated fatty acids and lysoPC linked to the reduction of its antiatherogenic functions. These sPLA(2)-mediated modifications of plasma lipoproteins might be relevant to the pathogenesis of atherosclerosis.

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Intussusceptive capillary growth, or nonsprouting angiogenesis is involved in the postinjury angiogenesis in the glomeruli, in which process mesangial cells as well as endothelial cells may play important roles.