GLYCOLALDEHYDE-MODIFIED LOW-DENSITY-LIPOPROTEIN LEADS MACROPHAGES TO FOAM CELLS VIA THE MACROPHAGE SCAVENGER RECEPTOR

It was shown that proteins modified with advanced glycation end produc ts (AGE) are effectively endocytosed by macrophages or macrophage-deri ved cells in vitro, and immunohistochemical studies involving anti-AGE antibodies demonstrated the accumulation of AGE-modified proteins (AG E-proteins) in macrophage-derived foam cells in human atherosclerotic lesions in situ, suggesting the involvement of AGE-modified LDL in the atherogenic process in vivo. To examine this suggestion, LDL was modi fied with glycolaldehyde, a highly reactive intermediate of the Mailla rd reaction, Physicochemically, glycolaldehyde-modified LDL (GA-LDL) w as characterized by increases in negative charge, fluorescence intensi ty, and reactivity to anti-AGE antibodies, properties highly similar t o those of AGE-proteins. The cellular interaction of GA-LDL with mouse peritoneal macrophages showed that GA-LDL was specifically recognized and endocytosed, followed by lysosomal degradation. The endocytic upt ake of GrA-LDL by these cells was competitively inhibited by acetylate d LDL (acetyl-LDL), and the endocytic degradation of acetyl-LDL was al so competed for by GA-LDL. Furthermore, incubation of GA-LDL with thes e macrophages and Chinese hamster ovary cells overexpressing the macro phage scavenger receptor (MSR), but not with peritoneal macrophages fr om MSR-knockout mice, led to the intracellular accumulation of cholest eryl esters (CE). These results raised the possibility that AGE-modifi ed LDL, if available in situ, is taken up by macrophages mainly via MS R and then contributes to foam cell formation in early atherosclerotic lesions.