Atherosclerosis, the leading cause of death in the U.S., begins with accumulation of monocyte/macrophages in the subendothelial space and their acquisition of stores of cholesterol esters. The long-term goal of the studies proposed here is to enhance our understanding of the mechanisms by which macrophages take up lipids and the mechanisms by which they mobilize them, in the hope that these studies will suggest new ways of intervening to slow atherogenesis. Native LDL is taken up too slowly by macrophages to generate foam cells and this has led to a search for modified forms of LDL that might be taken up more avidly. We have recently shown that aggregates of LDL generated by surface denaturation are taken up by macrophages 3-8 times more rapidly than native LDL. Preliminary studies indicate that te LDL receptor (apo B/E receptor) is involved and that the uptake has some of the qualities of phagocytosis. Since concentrations of LDL are high in developing lesions and since the lifetime of LDL in the intima is long, self-aggregation of LDL could play a role in fatty streak formation. We propose to characterize in detail this self- aggregation of LDL; to explore the conditions that favor it or that inhibit it; to test whether aggregates of LDL with other macromolecules may be taken up in part by an analogous mechanism involving the B/E receptor; and to explore the possibilities that aggregation of this kind may occur in the artery wall. We also propose to continue our studies of the cholesterol ester cycle in the macrophage, examining in detail the possibility that uptake of oxidatively modified LDL may influence the neutral cholesterol esterase or acyl CoA-cholesterol acyltransferase activity. Finally, we will study the potential impact of the macrophage on endothelial cell integrity. It has been proposed that toxic materials produced by the macrophage may lead to the loss of overlying endothelial cells and trigger the transition of the fatty streak to the more advanced lesion. We will study the ways in which oxidatively modified LDL and other ligand that interact with the scavenger receptor may alter the rates of secretion of potentially toxic products from the macrophage (including superoxide anion and a series of lytic enzymes).

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Metabolism Study Section (MET)
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University of California San Diego
Schools of Medicine
La Jolla
United States
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Ziolo, M T; Katoh, H; Bers, D M (2001) Positive and negative effects of nitric oxide on Ca(2+) sparks: influence of beta-adrenergic stimulation. Am J Physiol Heart Circ Physiol 281:H2295-303
Khoo, J C; Miller, E; Pio, F et al. (1992) Monoclonal antibodies against LDL further enhance macrophage uptake of LDL aggregates. Arterioscler Thromb 12:1258-66
Rosenfeld, M E; Khoo, J C; Miller, E et al. (1991) Macrophage-derived foam cells freshly isolated from rabbit atherosclerotic lesions degrade modified lipoproteins, promote oxidation of low-density lipoproteins, and contain oxidation-specific lipid-protein adducts. J Clin Invest 87:90-9
Parthasarathy, S; Khoo, J C; Miller, E et al. (1990) Low density lipoprotein rich in oleic acid is protected against oxidative modification: implications for dietary prevention of atherosclerosis. Proc Natl Acad Sci U S A 87:3894-8
Khoo, J C; Miller, E; McLoughlin, P et al. (1990) Prevention of low density lipoprotein aggregation by high density lipoprotein or apolipoprotein A-I. J Lipid Res 31:645-52
Goldberg, D I; Khoo, J C (1990) Stimulation of a neutral cholesteryl ester hydrolase by cAMP system in P388D1 macrophages. Biochim Biophys Acta 1042:132-7
Khoo, J C; Miller, E; McLoughlin, P et al. (1989) Cholesterol esterification as a limiting factor in accumulation of cell cholesterol: a comparison of two J774 macrophage cell lines. Biochim Biophys Acta 1012:215-7
Khoo, J C; Miller, E; McLoughlin, P et al. (1988) Enhanced macrophage uptake of low density lipoprotein after self-aggregation. Arteriosclerosis 8:348-58
Goldberg, D I; Khoo, J C (1988) Secretion of the lysosomal acid triacylglycerol hydrolase precursor by J774 macrophages. Biochim Biophys Acta 960:200-9
Goldberg, D I; Khoo, J C (1987) Regulation of lipoprotein lipase secretion by mouse peritoneal macrophages. Biochem Biophys Res Commun 142:1-6

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