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.

Public Health 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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
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Domanski, Michael
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Case Western Reserve University
Schools of Arts and Sciences
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Biswas, Sudipta; Xin, Liang; Panigrahi, Soumya et al. (2016) Novel phosphatidylethanolamine derivatives accumulate in circulation in hyperlipidemic ApoE-/- mice and activate platelets via TLR2. Blood 127:2618-29
Panigrahi, Soumya; Ma, Yi; Hong, Li et al. (2013) Engagement of platelet toll-like receptor 9 by novel endogenous ligands promotes platelet hyperreactivity and thrombosis. Circ Res 112:103-12
Zhang, Guo-Fang; Sadhukhan, Sushabhan; Ibarra, Rafael A et al. (2012) Metabolism of ?-hydroxybutyrate in perfused rat livers. Biochem J 444:333-41
Gu, Xiaodong; Salomon, Robert G (2012) Fragmentation of a linoleate-derived ?-hydroperoxy-?,?-unsaturated epoxide to ?-hydroxy- and ?-oxo-alkenals involves a unique pseudo-symmetrical diepoxycarbinyl radical. Free Radic Biol Med 52:601-606
Alves, Eduardo; Bartlett, Paula J; Garcia, Celia R S et al. (2011) Melatonin and IP3-induced Ca2+ release from intracellular stores in the malaria parasite Plasmodium falciparum within infected red blood cells. J Biol Chem 286:5905-12
Salomon, Robert G; Gu, Xiaodong (2011) Critical insights into cardiovascular disease from basic research on the oxidation of phospholipids: the ?-hydroxyalkenal phospholipid hypothesis. Chem Res Toxicol 24:1791-802
Tang, Xiaoxia; Sayre, Lawrence M; Tochtrop, Gregory P (2011) A mass spectrometric analysis of 4-hydroxy-2-(E)-nonenal modification of cytochrome c. J Mass Spectrom 46:290-7
Choi, Jaewoo; Laird, James M; Salomon, Robert G (2011) An efficient synthesis of ýý-hydroxy-ýý,ýý-unsaturated aldehydic esters of 2-lysophosphatidylcholine. Bioorg Med Chem 19:580-7
Harris, Stephanie R; Zhang, Guo-Fang; Sadhukhan, Sushabhan et al. (2011) Metabolism of levulinate in perfused rat livers and live rats: conversion to the drug of abuse 4-hydroxypentanoate. J Biol Chem 286:5895-904
Tomcik, Kristyen; Ibarra, Rafael A; Sadhukhan, Sushabhan et al. (2011) Isotopomer enrichment assay for very short chain fatty acids and its metabolic applications. Anal Biochem 410:110-7

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