Abstract 16609: The Receptor for Advanced Glycation Endproducts (RAGE) Regulates Macrophage Cholesterol Efflux
RAGE plays a critical role in atherosclerosis via multiple mechanisms such as increased inflammation within the aortic wall; vascular endothelial dysfunction; monocytes/macrophages accumulation; and progression of atherosclerosis plaques, particularly in diabetes. Our previous studies showed that RAGE modulates inflammation through NF-kB, TGF-β/Rock1, MAPKs, JNK/ERK, and via the formin mDia1 (the RAGE cytoplasmic domain interacting molecule essential for RAGE-mediated signaling). In the present study, we tested the hypothesis that RAGE contributes to accelerated atherosclerosis at least in part via lipid homeostasis, particularly modulation of macrophage cholesterol efflux. To test this concept, we labeled primary murine bone marrow-derived macrophages (BMDMs) from four groups of mice; C57BL/6 Non diabetes, C57BL/6 diabetes, RAGE null Non diabetes and RAGE null diabetes, with ³H-cholesterol, and proceeded with cholesterol efflux assays to APOA1 and HDL. Our data (see the table below) reveal that macrophages from RAGE null mice display significantly higher cholesterol efflux rate compared to macrophages from C57BL/6 mice, especially under diabetic conditions. We tested cholesterol efflux in human THP-1 macrophages in either euglycemic (5.5mM D-glucose) vs. diabetes-relevant (25mM D-glucose) conditions. We found that THP-1 cells grown in high glucose revealed decreased cholesterol efflux to ApoA1 or HDL and that knockdown of RAGE using siRNA resulted in significantly increased cholesterol efflux vs. scramble siRNAs in both eu- and hyperglycemic conditions. In parallel, we found that expression of mRNA levels for cholesterol transporters ABCG1 and ABCA1 were significantly higher in RAGE null vs. wild-type BMDMs (6.4-fold and 4.9-fold respectively). In conclusion, we postulate that RAGE regulates non-diabetic and especially diabetic atherosclerosis, at least in via suppression of macrophages cholesterol efflux..
- © 2012 by American Heart Association, Inc.