Lipoprotein-proteoglycan complexes from atherosclerotic lesions promote cholesteryl ester accumulation in human monocytes/macrophages.

Abstract

Lipoprotein-proteoglycan complexes from human atherosclerotic lesions were studied to determine their ability to stimulate cholesteryl ester accumulation in human monocytes/macrophages. Complexes containing apolipoprotein (apo) B lipoproteins and proteoglycans were extracted from fatty streaks and fibrous plaque lesions of human aortas by extraction with 0.15 M NaCl. Fractionation of the complex with Bio-Gel A-50m yielded a single fraction from fatty streaks and two fractions from fibrous plaques. The complexes were further purified by antl-apo B affinity chromatography and analyzed for apolipoproteins, lipids, and glycosaminoglycans. Apo B was the only apolipoprotein present in the complexes. Although the complexes from fatty streaks and fibrous plaques contained varying proportions of hyaluronic acid, chondroitin 6-sulfate, and dermatan sulfate, heparin was present in only the fibrous plaque complexes. All three lipoprotein-proteogtycan complexes increased the rate of incorporation of [ M C]oleate into cholesteryl [ 14 C]oleate and stimulated cholesteryl ester accumulation in monocytes/macrophages. However, the complexes from fibrous plaques were more potent than those from fatty streaks in this regard. Cholesteryl ester synthesis that is mediated by the uptake of the complexes was dose dependent and showed apparent saturation, suggesting that cell surface binding may be required. Chloroquine, a lysosomotropic agent, inhibited cholesteryl ester synthesis that is induced by the complexes, indicating that lysosomal hydrolysis was essential. Cholesteryl ester synthesis that is mediated by the complexes was inhibited 70-79% by polyinosinic acid. Furthermore, excess unlabeled fibrous plaque complexes significantly inhibited the binding and interaalization of in vitro In vitro, low density lipoprotein (LDL) does not induce cholesteryl ester accumulation in macrophages from different sources, including human

Retention of Oxidized LDL by Extracellular Matrix Proteoglycans Leads to Its Uptake by Macrophages

“…12,46 In the present study, we used an ECM secreted by macrophages. The ECM present in the atheroma is likely to be a mixture of products secreted from all 3 types of cells that are present in the arterial wall.…”

Role of Oxidative Modifications in Atherosclerosis

“…Retained LDL is a substrate for sphingomyelinase (1074) that may generate ceramides that are known to promote apoptosis and mitogenesis (357,455). Most importantly, however, and as pointed out earlier, aggregated LDL is avidly internalized by macrophages and smooth muscle cells (440), thereby supporting foam cell formation without the need for LDL oxidation (991). Such at least initially LDL oxidationindependent formation of foam cells could explain why in human aortic lesions nonoxidized lipids accumulate before oxidized lipids as disease progresses (966).…”

“…Once retained within the arterial wall, LDL can form microaggregates (667,931), perhaps through the action of secretory sphingomyelinase (1074), an enzyme that also generates ceramides that mediate apoptosis and mitogenesis (357,455), as well as lysosomal enzymes such as cathepsin D and lysosomal acid lipase (350). Most importantly, aggregated LDL is avidly taken up by macrophages and smooth muscle cells (440) and thus can support foam cell formation (991). Thus many features of atherosclerosis can be attributed to enhanced retention of LDL within the arterial wall and its association with proteoglycans.…”

Sphingomyelinase Induces Aggregation and Fusion, but Phospholipase A2 Only Aggregation, of Low Density Lipoprotein (LDL) Particles

“…Indeed, complexes of apolipoprotein B-100 (apoB-100) containing lipoproteins and proteoglycans can be isolated from fatty streaks and fibrous plaques in the human aorta (3). Since a subendothelial proteoglycan-rich layer is present in all arteries, the atherosclerotic areas have been suggested to contain proteoglycans with a unique structure that favors entrapment of LDL (4,5).…”