No abstract

Oxidative modification of low density lipoprotein (LDL) enhances its potential atherogenicity in several ways, notably by enhancing its uptake into macrophages. In vivo studies in the rabbit show that inhibition of LDL oxidation slows the progression of atherosclerotic lesions. In the present studies, rabbits were fed either a newly developed variant sunflower oil (Trisun 80), containing more than 80% oleic acid and only 8% linoleic acid, or conventional sunflower oil, containing only 20% oleic acid and 67% linoleic acid. LDL isolated from the plasma of animals fed the variant sunflower oil was highly enriched in oleic acid and very low in linoleic acid. These oleate-rich LDL particles were remarkably resistant to oxidative modification. Even after 16-hr exposure to copper-induced oxidation or 24-hr incubation with cultured endothelial cells, macrophage uptake of the LDL was only marginally enhanced. The results suggest that diets sufficiently enriched in oleic acid, in addition to their LDL-lowering effect, may slow the progression of atherosclerosis by generating LDL that is highly resistant to oxidative modification.

Previous studies have established that incubation of low density lipoprotein (LDL) with cultured endotheHal cells (EC) converts it to a new form (EC-modified LDL) that is now recognized by a specific receptor on macrophages (the acetyl LDL receptor) and is taken up and degraded 3-10 times more rapidly than native LDL (biological modification). The formation of EC-modified LDL depended on generation of free radicals with consequent peroxidation of LDL lipids and was accompanied by extensive hydrolysis of LDL phosphatidylcholine at the 2-position. The present studies show that p-bromophenacyl bromide, a site-specific irreversible inhibitor of phospholipase A2 activity, blocks this hydrolysis and, at the same time, the enhanced macrophage degradation. We show further that during EC modification the apoprotein B of LDL undergoes considerable modification and that this also is prevented by the phospholipase inhibitor. Finally, as reported previously, changes similar to those observed on incubation of LDL with EC can be induced by incubation in the absence of cells but in the presence of a sufficiently high concentration of Cu2+. This also is accompanied by hydrolysis of phosphatidylcholine at the 2-position and breakdown of apoprotein B. These changes are also inhibited by p-bromophenacyl bromide, suggesting the presence of a phospholipase A2 activity associated with LDL as it is isolated. A hypothesis is presented linking lipid peroxidation, phosphatidylcholine hydrolysis, and changes in the LDL apoprotein during EC modification.Many or most of the lipid-laden foam cells of atherosclerotic lesions are derived from monocyte/macrophages (1-3). Yet, paradoxically, native low density lipoprotein (LDL) is recognized poorly by cultured macrophages and does not produce cholesterol ester accumulation in such cells in culture (4). Previously we have described a biological modification of LDL that converts it to a form recognized by macrophages and that leads to greatly enhanced cellular uptake and promotion of cholesterol ester accumulation (5-8). In part, the enhanced uptake is mediated via the "scavenger" receptorthe acetyl LDL receptor (4)-which also specifically recognizes several chemically modified forms of LDL (9, 10). The biological modification is effected by simply incubating native LDL overnight in the presence of cultured endothelial cells (EC) (5) or smooth muscle cells (7). The product, designated EC-modified LDL (EC-LDL), shows an increase in negative charge and hydrated density and is degraded less rapidly by the native LDL receptor (7). All of these changes were recently shown to be obligatorily linked to free radicalmediated peroxidation of LDL and to be accompanied by extensive hydrolysis of LDL phosphatidylcholine (PtdCho) to lyso-PtdCho (I-PtdCho) through apparent phospholipase A2 activity (8). All of the compositional changes, as well as the biological modification (defined here as those changes that induce the increased rate of degradation of EC-LDL by macrophages), were blocked by antioxidan...

Recent progress in molecular medicine has provided important tools to identify antigen-specific T cells. In most cases, the approach is based on oligomeric combinations of recombinant major histocompatibility complex-peptide complexes fixed to various rigid supports available for binding by the T-cell receptor. These tools have greatly increased our insight into mechanisms of immune responses mediated by CD8+ T cells. Examples of the diverse fields of application for this technology include immunization, viral infections and oral tolerance induction.

Supplementation of vitamin E in NIDDM leads to enrichment of LDL and LDL subfractions and reduced susceptibility to oxidation. Despite a greater percentage increase in vitamin E content in small dense LDL, it remained substantially more susceptible to oxidation than was buoyant LDL. This suggests that dense, LDL may gain less protection against oxidation from antioxidant supplementation than does larger, more buoyant LDL. In contrast to previous reports, vitamin E supplementation did not reduce glycation of intracellular or plasma proteins.