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.)
Many of the discussed results come from empirical experiments performed with in vitro models whose relevance to the complex environment of the intima is limited. However, they are consistent with the line of reasoning that intima PGs interact specifically with apoB lipoproteins and contribute to their retention. This could provide the residence time and the initial alterations of the lipoproteins that favor their further modifications by oxidative processes and hydrolytic enzymes. Products of such modifications, and the modified particles, may be stimuli for changes in the functionality of endothelium, smooth muscle cells, and macrophages. The focal synthesis of PGs with high affinity for apoB lipoproteins could make the phenomena chronic. Clinical and laboratory studies indicate that dense LDL, poor in surface polar lipids, is associated with an atherogenic phenotype. Particles with these properties may contribute to the disease via its high affinity for arterial PGs. This affinity can be modulated by diet, lifestyle, and lipid-lowering drugs.
There is much interest in the significance of apolipoproteins and proteins that are noncovalently associated with lipoproteins. It is possible that the high ionic strength used for isolation of lipoproteins with KBr and NaI could alter the pattern of associated exchangeable proteins. Here we describe lipoprotein classes fractionation from up to 0.5 ml of serum or plasma with buffers of physiological ionic strength and pH prepared with deuterium oxide (D 2 O) and sucrose. An advantage of the D 2 O/sucrose procedure was that the lipoproteins could be directly analyzed by the techniques described without need for desalting. We compared the isolated lipoproteins with those obtained using ultracentrifugation in KBr from the same plasma pool. Electrophoretic homogeneity of the lipoproteins was very similar using the two methods, as well as their lipid composition evaluated by HPLC. Two-dimensional electrophoresis and surface-enhanced laser adsorption/ionization time-offlight mass spectrometry indicated that the patterns of exchangeable proteins of VLDL isolated using with the two procedures were very similar. However, significant differences were found in the profiles of LDL and HDL, indicating that the D 2 O/sucrose method allowed a more complete characterization of its exchangeable apolipoproteins and proteins.-Ståhlman, M., P. Davidsson, I. Kanmert, B. Rosengren, J. Borén, B. Fagerberg, and G. Camejo. Proteomics and lipids of lipoproteins isolated at low salt concentrations in D 2 O/sucrose or in KBr. J. Lipid Res. 2008. 49: 481-490.
The reversible interaction of low density lipoprotein (LDL) with arterial chondroitin sulfate proteoglycans (CSPGs) or glycosaminoglycans (GAGs) selects LDL particles with a high affinity for sulfated GAGs and also induces modifications in apolipoprotein B (apo B) and the lipid organization of the lipoprotein. In the present work we studied the effect that the reversible interaction with sulfated polysaccharides has on the susceptibility of LDL to in vitro oxidation. For this purpose soluble, nonaggregated CSPG-or GAG-treated LDL was subjected to oxidation in the presence of 5 fiM CuSO 4 for as long as 48 hours. The rate of formation of thiobarbituric acid-reactive substances, the decrease in isoelectric point, the increase in relative electrophoretic mobility of LDL, the higher degradation rate by human macrophages, and the lower degradation rate by human arterial smooth muscle cells showed that LDLs exposed to CSPGs and GAGs were significantly more susceptible to oxidation than native LDL. Results from competition experiments indicate that C6S-treated LDL after 4 hours of oxidation is taken up via the acetylated LDL receptor in human macrophages. Coincubation of lipoproteins with human macrophages or human arterial smooth muscle cells for 24 hours also indicated that C6S-treated LDL was more susceptible to cell-induced modifications than native LDL. The occurrence in vivo of similar processes may contribute to focal retention, increased rate oxidation of LDL in the arterial intima, and foam cell formation during atherogenesis. ( 11 The interaction of low density lipoprotein (LDL) with human arterial chondroitin sulfate proteoglycans (CSPGs) or glycosaminoglycans (GAGs) induces changes in the apo B lipoprotein and lipid organization that can be observed by
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