Endocytic uptake of AGE-modified low-density lipoprotein by macrophages leads to cholesteryl ester accumulation in vitro

Abstract

Recent studies disclosed that proteins modified by advanced glycation endproducts (AGE) are taken up by macrophages or macrophage-derived cells by the macrophage scavenger receptor (MSR) in vitro and that AGE-proteins are accumulated in foam cells in the human atherosclerotic lesions in vivo , suggesting a possibility that AGE-modified low density lipoprotein (AGE-LDL) in situ might be involved in atherogenic processes in vivo . As a first step, AGE-LDL was prepared by incubating LDL with glycolaldehyde (GA), a highly reactive intermediate of the Maillard reaction. GA-modified LDL (GA-LDL) is characterized by an increase in negative charge, fluorescent intensity and reactivities to anti-AGE antibodies, suggesting that these physicochemical and immunochemical properties of GA-LDL were highly similar to those of AGE-proteins. Furthermore, studies of cellular interaction of GA-LDL with mouse peritoneal macrophages showed that GA-LDL is recognized and endocytosed, followed by intralysosomal degradation by these cells. Endocytic uptake of GA-LDL by these cells was competitively inhibited by acetylated LDL (acetyl-LDL), a representative ligand for MSR. Endocytic degradation of 125 I-acetyl-LDL was competed for by GA-LDL. Furthermore, incubation of GA-LDL effectively converted them into foam cells. Similar results were obtained from CHO cells overexpressing MSR. These results suggest that LDL modified by AGE in situ is taken up by macrophages mainly via MSR and contributed to foam cell formation in the early atherosclerotic lesions.