Abstract 5572: RAGE Signaling in Macrophages Contributes to Atherosclerosis in ApoE Null Mice
Macrophage-derived foam cell formation is an essential process in atherosclerosis. RAGE (Receptor for Advanced Glycation Endproducts) and its ligands play a role in atherosclerotic lesion formation, especially in diabetes. RAGE is expressed in monocytes/macrophages and previous studies revealed key roles for RAGE in macrophage migration and production of cytokines. To test the role of RAGE signaling in monocytes/macrophages, we developed transgenic mice expressing cytoplasmic domain-deleted RAGE (dominant-negative RAGE (DN-RAGE) in macrophages under control of the Macrophage Scavenger Receptor-type A promoter to study the role of RAGE in atherosclerosis (noted as MSR-DN-RAGE). Four groups of mice, all in apoE−/− background and fed with normal chow diet, were tested under diabetic (D) and non diabetic ND) conditions. At age 24 weeks, lesion areas by en face analysis of entire aorta and at the aortic sinus were significantly reduced in MSR-DN-RAGE+/apoE−/− vs. apoE−/− mice (in both ND and D) (Table⇓). Immunohistochemistry of lesions demonstrated significantly reduced % of macrophages/lesion area in both ND and D MSR-DN-RAGE+/apoE−/− vs. apoE−/− mice, and in D mice, significantly lower % smooth muscle cells/lesion area in MSR-DN-RAGE+/apoE−/− vs. apoE−/− mice (Table⇓). The % T cells/lesion area were not different among the ND and D groups (Table⇓). We conclude that macrophage RAGE signaling critically contributes to atherosclerosis in apoE−/− mice irrespective of the diabetic state.