The lipid-laden foam cells of atheromatous lesions belong in part to the monocytemacrophage lineage. It is known that the lipids of foam cells are predominantly cholesteryl ester, but the precise in vivo mechanism for cholesteryl ester accumulation in macrophages is unknown. In vitro, macrophages accumulate cholesteryl ester by taking up several chemically and biologically modified forms of low density lipoprotein (LDL) and LDL-dextran sulfate complex by receptor-mediated processes. Large molecular weight proteoglycans (PG) are natural constituents of arterial wall, which readily form complexes with LDL. We have now isolated lipoprotein-PG complexes from atherosclerotic lesions in both humans and experimental animals. This research will explore mechanisms of in vivo macrophage foam cell formation. Our initial studies show that LDL-PG complex promotes cholesteryl ester deposition in mouse peritoneal macrophages. Therefore, we hypothesize that the uptake of lipoproteins complexed to arterial wall PG by human monocyte-macrophages will lead to intracellular cholesterol accumulation and subsequent foam cell formation. The research will investigate the potential of lipoprotein- PG complexes isolated from human atherosclerotic lesions to transform human monocyte-macrophages into foam cells. Discreet lipoprotein-PG complexes will be isolated from human atherosclerotic lesions and characterized. In vitro complexes will be prepared using 125 I-labeled LDL and bovine aorta PG. Human monocyte macrophages will be incubated with lipoprotein-PG complexes from fatty streaks and fibrous plaques, and cholesteryl ester synthesis and accumulation will be monitored. In order to determine whether the uptake of lipoprotein-PG complexes by macrophages contributes to foam cell formation in vivo, the metabolism of LDL-PG complex by foam cells will be investigated. The mechanism of uptake of the complex will be examined by performing 125 I-LDL-PG complex binding and degradation studies under conditions that are known to affect receptor-mediated uptake process. In addition, effect of maturation, cell density, serum and macrophage secretory products on the metabolism of the complexes. These studies should provide valuable information on foam cell formation and the important role of PG in atherosclerosis.
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