Abstract 5672: Deletion of Bone Marrow Derived Receptor for Advanced Glycation End-products (RAGE) Does Not Attenuate Plaque Formation but Inhibits Plaque Progression in a Mouse Model of Advanced Atherosclerosis
Background and Hypothesis: The multiligand receptor for advanced glycation end products (RAGE) of the immunoglobulin superfamily is expressed on multiple cell types implicated in the immune-inflammatory response and in atherosclerosis. We sought to determine the role that bone marrow derived RAGE plays in different stages of atherosclerotic lesion development in apolipoprotein E deficient (apoE−/−) mice.
Methods and Results: 7 and 23 week apoE−/− mice were lethally irradiated and given bone marrow from RAGE null (RAGE−/−//apoE−/−) or RAGE−/−//apoE−/− mice to create double knock out chimeras. After 16 weeks on a standard chow diet the mice were sacrificed and atherosclerotic lesion development was evaluated. Plaques in the aortic root of the young mice showed no significant difference in maximum plaque size (217 470±17 480 μm2 for the RAGE−/−//apoE−/− mice compared to 244 764±45 840 μm2) whereas plaques from the older innominate artery of Rage−/−/apoE−/− mice had significantly smaller maximum plaque area compared to the Rage−/−/apoE−/− mice (83 384±17 981 μm2 compared to 136 041±13604 μm2, p<.05) as well as reduced average necrotic core area (35 582±4 797μm2 compared to 55 604±6 523 μm2, p<.05). Reduced plaque size and more stable plaque morphology was associated with significant decreases in the expression of important atherogenic mediators including VCAM-1, ICAM-1, and MCP-1. Accumulation of the RAGE ligand HMGB-1 was also significantly reduced within the lesions of the Rage−/−/apoE−/− mice.
Conclusions: This study demonstrates that bone marrow derived RAGE is an important factor in the progression of atherosclerotic plaque development by causing increased expression of pro-atherosclerotic mediators. It provides evidence that RAGE could be a potential target for clinical treatment of advanced atherosclerosis.