HUMAN MONOCYTE-DERIVED MACROPHAGES BIND LOW-DENSITY-LIPOPROTEIN PROTEOGLYCAN COMPLEXES BY A RECEPTOR DIFFERENT FROM THE LOW-DENSITY-LIPOPROTEIN RECEPTOR

We have shown recently that lipoprotein proteoglycan complexes isolated from human atherosclerotic lesions stimulated cholesteryl ester synthesis in human monocyte-derived macrophages [Vijayagopal. Srinivasan, Radhakrishnamurthy and Berenson (1992) Arterioscler. Thromb. 12, 237 249]. The present study was conducted to determine the mechanism of cellular uptake of the complexes. A chondroitin sulphate-dermatan sulphate proteoglycan was isolated from normal human aorta and complexed to I-125-labelled human low-density lipoprotein (LDL). The binding and degradation of I-125-LDL-proteoglycan complex were then studied in human monocyte-derived macrophages. The specific binding and degradation of the complex showed saturability and concentration-dependency. The K(d) for binding was 1.5 x 10(-8) M, which was greater than that reported for LDL in monocyte-derived macrophages. Binding of the complex was not subject to down-regulation. Chloroquine inhibited degradation of the complex and the resultant stimulation of cholesteryl ester synthesis. Limited treatment of macrophages with proteolytic enzymes abolished binding and degradation of the complex significantly. Macrophages bound I-125-methyl-LDL proteoglycan complex to the same extent as I-125-LDL-proteoglycan complex. Excess LDL and proteoglycan did not compete against the binding of the complex; however, excess acetyl-LDL competed for 61% of the binding. Likewise, excess LDL proteoglycan complex inhibited the binding of I-125-acetyl-LDL by 64%. Polyinosinic acid and cytochalasin D inhibited the binding of I-125-LDL-proteoglycan complex by 60% and 36% respectively. Compared with that of acetyl-LDL, the degradation of LDL-proteoglycan complex was retarded in human macrophages. The results indicate that the uptake of LDL-proteoglycan complex in human monocyte-derived macrophages is not mediated through binding to the LDL receptor; but occurs predominantly via the scavenger receptor, with phagocytosis playing a minor role in the process.