The Receptor for Advanced Glycation End Products Mediates the Chemotaxis of Rabbit Smooth Muscle Cells

We recently demonstrated immunologically the intraccllular accumulation of advanced glycation end products (AGEs) in foam cells derived from smooth muscle cells (SMCs) in advanced atherosclerotic lesions. To understand the mechanism of AGE-accumulation in these foam cells, the interaction of AGE-proteins with rabbit cultured arterial SMCs was studied in the present study. In experiments at 4°C, 125I-AGE-bovine serum albumin (AGE-BSA) showed dose-dependent saturable binding to SMCs with an apparent dissociation constant (Kd) of 4.0 μ/mL. In experiments at 37°C, AGE-BSA underwent receptor-mediated endocytosis and subsequent lysosomal degradation. The endocytic uptake of 125I-AGE-BSA was effectively inhibited by unlabeled AGE-proteins, but not by acetylated low density lipoprotein (LDL) and oxidized LDL, well-known ligands for the macrophage scavenger receptor (MSR). Moreover, the binding of 125I-AGE-BSA to SMCs was affected neither by amphoterin, a ligand for one type of the AGE receptor named RAGE, nor by 2-(2-Furoyl)-4(5)-(2-furanyl)-1 H-imidazolc-hexanoic acid-BSA (FFI-BSA), a ligand for the other AGE receptors called p60 and p90, indicating that the endocytic uptake of AGE-proteins by SMCs is mediated by an AGE receptor distinct either from MSR, RAGE, p60 or p90. To examine the functional role of (his AGE receptor, the effects of AGE-BSA on the migration of SMCs were tested. Incubation with 1-50 μg/mL of AGE-BSA resulted in significant dose-dependent cell migration. The AGE-BSA-induced SMCs migration was chemotactic in nature, and was significantly inhibited (−80%) by an antibody against transforming growth factor-β (TGF-β), and the amount of TGF-β secreted into the culture medium from SMCs by AGE-BSA was 7-fold higher than that of control, indicating that TGF-β is involved in the AGE-induced SMCs chemotaxis.