Deletion of bone marrow-derived receptor for advanced glycation end products inhibits atherosclerotic plaque progression

Abstract

The multiligand receptor for advanced glycation end products (RAGE) of the immunoglobulin superfamily is expressed on multiple cell types implicated in the inflammatory response in atherosclerosis. We sought to determine the role of bone marrow-derived RAGE in different stages of atherosclerotic development in apolipoprotein E-deficient mice (apoE(-/-)). Seven- and 23-week-old apoE(-/-) mice (n = 40) were lethally irradiated and given bone marrow from RAGE null (RAGE(-/-)/apoE(-/-)) or RAGE-bearing (RAGE(+/+)/apoE(-/-)) mice to apoE(-/-) mice to generate double knockout bone marrow chimera (RAGE(-/-)/apoE(-/-bmc) and RAGE(+/+)/apoE(-/-bmc)-, respectively). After 16 weeks on a standard chow diet, mice were sacrificed and atherosclerotic lesion formation was evaluated. Plaques in the aortic root of the young mice showed no significant difference in maximum plaque size (217,470 ± 17,480 μm(2) for the RAGE(-/-) /apoE(-/-bmc) mice compared to 244,764 ± 45,840 μm(2)), whereas lesions in the brachiocephalic arteries of the older RAGE(-/-)/apoE(-/-bmc) mice had significantly smaller lesions (94,049 ± 13,0844 μm(2) vs. 145,570 ± 11,488 μm(2), P < 0.05) as well as reduced average necrotic core area (48,600 ± 9220 μm(2) compared to 89,502 ± 10,032 μm(2), P < 0.05) when compared to RAGE(+/+)/apoE(-/-bmc) mice. Reduced plaque size and more stable plaque morphology was associated with significant reduced expression of VCAM-1, ICAM-1 and MCP-1. Accumulation of the RAGE ligand HMGB-1 was also significantly reduced within the lesions of RAGE(-/-)/apoE(-/-bmc) mice. This study demonstrates that bone marrow-derived RAGE is an important factor in the progression of atherosclerotic plaques.