Lipoprotein-proteoglycan complexes induce continued cholesteryl ester accumulation in foam cells from rabbit atherosclerotic lesions.

Abstract

We studied the metabolism of lipoprotein-proteoglycan complexes by macrophage-derived foam cells. Foam cells were isolated from atherosclerotic rabbit aortas. ApoB-lipoproteinproteoglycan complex was isolated from human aorta fibrous plaque lesions and LDL-proteoglycan complex was formed in vitro. Both in vitro and in vivo complexes stimulated cholesteryl ester synthesis in foam cells by a dose-dependent, saturable process that resulted in the intracellular accumulation of cholesteryl ester. Stimulation ofcholesteryl ester synthesis was linear with time over a 32-h period. Polyinosinic acid inhibited the stimulation of cholesteryl ester synthesis by the complexes by 32-37%, whereas cytochalasin D only produced a 6-16% inhibition. Foam cells degraded '25I-LDL-proteoglycan complex and 125I-acetyl LDL in a saturable, dose-dependent manner. Excess unlabeled acetyl-LDL inhibited the degradation of '251-LDL-proteoglycan complex by 52%, while LDL had no effect. Similarly, excess unlabeled complex suppressed the degradation of '251-acetyl-LDL by 48%. Foam cells degraded 1251. methyl-LDL-proteoglycan complex to the same extent as 1251_ LDL-proteoglycan complex. These results show that foam cells from atherosclerotic lesions metabolize lipoprotein-proteoglycan complexes predominantly via receptor-mediated endocytosis and consequently continue to accumulate intracellular cholesteryl ester. (J. Clin. Invest. 1993. 91:1011-1018

Intrinsic Fluorescence and Diffuse Reflectance Spectroscopy Identify Superficial Foam Cells in Coronary Plaques Prone to Erosion

“…24,28 It is believed that hyaluronan promotes erosion by ways of receptor-mediated platelet adhesion and inflammatory cell recruitment, 7 and that SMC apoptosis causes the release of tissue factor, a key element of the extrinsic coagulation cascade. 29 We therefore suspect that SFCs, in addition to their direct actions, may promote plaque erosion through indirect mechanisms that involve the accumulation of proteoglycans, especially hyaluronan, 2,7,26,27 and SMC apoptosis. 28,29 …”

Subendothelial Proteoglycan Synthesis and Transforming Growth Factor Beta Distribution Correlate with Susceptibility to Atherosclerosis

“…This, in turn, increases uptake of the LDL-PG complexes by macrophages via scavenger receptors and leads to increased foam cell formation and lesion progression [20][21][22], A hallmark of atherosclerotic lesion development is increased deposition and accumulation of PGs, especially in the subendothelial zone of the intima [23,24], General ly, this increase in sulphated PGs occurs during the early and mid stages of lesion development with a decrease as lesions become more advanced and fibrotic [25,26].…”

Change of plasma lipoproteins by heparin-released lipoprotein lipase

“…Oxidized LDL can be taken up by macrophage scavenger receptors leading to foam cell formation, stimulation of monocyte and inhibition of macrophage chemotaxis, and cytotoxicity (Steinberg et al, 1989;Witztum, 1993). Other potential mechanisms of cellular uptake of cholesterol include phagocytic uptake of aggregated LDL by macrophages (Hurt and Camejo, 1987;Salisbury et al, 1985;Vijayagopal et al, 1993), or immune complexes of lipoproteins via Fc receptor of macrophages (Bierman, 1992;Klimov et al, 1985;Wi t z t u m , 1993).…”