Role Of Receptor For Advanced Glycation End Products (Rage) In Regression Of Diabetic Atherosclerosis

Atherosclerosis is a chronic inflammatory disorder. Both progression and regression of atherosclerosis are adversely affected by diabetes. A key player in these processes is Receptor for Advanced Glycation End Products (RAGE). RAGE is a multiligand cell surface macromolecule, which binds ligands enriched in atherosclerotic plaques, such as advanced glycation endproducts (AGEs). RAGE is expressed on a wide array of cell types implicated in cardiovascular disease, such as endothelial cells, and inflammatory cells such as macrophages. The cytoplasmic domain of RAGE binds to the formin molecule DIAPH1 and DIAPH1 is required for RAGE ligands to activate cell signaling responses. RAGE acts as a key mediator of oxidative and inflammatory signaling pathways that are involved in atherosclerosis. We tested mechanisms of impaired regression of atherosclerosis in a murine model of aorta transplantation and found that deletion of Ager or Diaph1 in diabetic mice recipients of Ldlr null mice atherosclerotic aortas accelerates atherosclerosis regression and significantly reduces the lesional macrophage content when compared to diabetic wild-type recipient mice. The antiatherosclerotic effects in diabetic Ager null mice and diabetic Diaph1 null mice include reduced RAGE ligand AGEs in transplanted aortas, with reduced expression of a range of proatherogenic factors, including reactive oxygen species and inflammatory cytokines implicated in leukocyte recruitment and activation. We employed RNA sequencing to identify the key transcriptional events by which RAGE mediates its effects in donor or recipient macrophages in diabetic regressing plaques. Our results suggest that critical gene expression profiles, including those genes involved in inflammation, endothelial dysfunction, oxidative stress, monocyte/macrophage fate (recruitment, differentiation, proliferation), signal transduction and lipid metabolism, are beneficially modulated, at least in part, via Ager deletion in atherosclerosis regression. Taken together, these data increase our understanding of the role of RAGE in diabetic atherosclerosis, particularly in macrophages, and may provide avenues for therapeutic strategies to accelerate regression of atherosclerosis in diabetes.