Abstract 532: The Receptor for Advanced Glycation End Products (RAGE) Suppresses Macrophage Cholesterol Transport in Diabetes
Diabetes is a leading cause of cardiovascular morbidity and mortality. In human subjects, diabetes suppresses macrophage cholesterol efflux capacity, at least in part via reduction in levels of the major cholesterol transporters, ABCA1 and ABCG1. We tested the hypothesis that the receptor for advanced glycation end products (RAGE) contributes to these processes. We report that ligand-RAGE interaction suppresses cholesterol efflux to ApoA1 and HDL in primary murine bone marrow-derived macrophages (BMDMs) and in human THP-1 cells, at least in part via downregulation of ABCA1 and ABCG1. In vivo, compared to cholesterol-loaded wild-type (WT) diabetic murine BMDMs, diabetic BMDMs devoid of Ager (gene encoding RAGE) displayed significantly higher reverse cholesterol transport (RCT) to plasma, liver and feces when injected into WT non-diabetic mice. In atherosclerotic plaques from mice devoid of both Ldlr and Ager and fed a high cholesterol diet, higher Abca1 and Abcg1 mRNA transcript levels were also observed compared to Ager-expressing LDL receptor null mice. RAGE ligand AGEs suppress ABCG1 promoter luciferase activity and transcription of ABCG1 through reduced binding of PPARgamma (PPARG) to PPARG-responsive elements in the ABCG1 promoter. These data reveal that RAGE contributes to dysregulation of macrophage cholesterol metabolism, particularly in diabetes. We infer that antagonism of RAGE may mitigate accelerated atherosclerosis in the diabetic state, at least in part due to modulation of impaired cholesterol transport.
Author Disclosures: G. Daffu: None. X. Shen: None. A. Abedini: None. L. Senatus: None. C. Hurtado del Pozo: None. R. Rosario: None. F. Song: None. R. Friedman: None. R. Ramasamy: None. A. Schmidt: None.
- © 2015 by American Heart Association, Inc.