Molecular Basis of Oxidative Modification of LDL

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Substantial evidence suggests that the accumulation and subsequent poor processing of oxidatively modi- fied low density lipoprotein (oxLDL) by macrophages in the arterial wall contributes to the initial stages of atherogenesis. Oxidative modification of LDL involves the derivatization of its constituent apolipoprotein B by reactive aldehydic breakdown products of lipid peroxidation, including HNE. The chemistry of protein adduction by these aldehydes is highly complex and includes cross-linking. A major breakthrough of the current funding period was the finding that uptake of oxLDL by macrophages may be largely mediated by the recognition of oxidized phospholipids in oxLDL by CD36. We further discovered that the HNE-like products (and their derivatives) resulting from "mirror-image" oxidation of the arachidonyl and linoleyl chains of phospholipids serve as CD36 ligands. Further studies are proposed to bring thorough definition to the structural basis of oxLDL recognition by and accumulation within macrophage cells. Recent pilot studies suggest that oxidized constituents in oxLDL may interfere not only with lipoprotein processing within, but also cholesterol efflux from macrophage cells exposed to oxLDL. A major new aim of the next funding period is to clarify the nature of the inhibitory effects of oxLDL on cholesterol efflux. Our working hypothesis is that oxidative changes to LDL contribute to its uptake into and deficient processing within macrophage cells, and that oxLDL itself or constituents emanating from it inhibit one or more mechanisms of cholesterol efflux, all of which together act as an important determinant of foam cell formation. We will continue to define lipoxidation-dependent protein adduction chemistry, including mass spectrometric approaches to identifying macrophage proteins that are particularly susceptible to modification as a result of exposure of these cells to oxLDL. This latter aim will be aided by continued development of immunochemical probes for specific adducts, also useful for identifying the nature of late-stage adducts present in human atheroma. The new work proposed continues to take advantage of the pooled expertise of three individual investigators at neighboring research institutions, particularly with respect to the application of novel structurally-specific reagents and tools to cell biological studies. RELEVANCE TO PUBLIC HEALTH In the initial stages of atherosclerosis, the main cholesterol-carrying lipoprotein in blood, LDL, becomes oxidatively damaged (oxLDL), resulting in an attempt by cells lining the artery wall to scavenge the oxLDL and break it down. Our research is aimed at understanding why there is an accumulation of cholesterol in these cells because of their inability to efficiently break down the oxLDL and clear the released cholesterol.