Abstract 471: Receptor for Advanced Glycation End Products, Reverse Transmigration and Impaired Regression of Diabetic Atherosclerosis
Cellular migration is fundamental processes linked to diverse pathological states including atherosclerosis and diabetes. RAGE is a multiligand cell surface macromolecule, which binds ligands such as advanced glycation endproducts. In evaluating the relationship between impaired regression of atherosclerosis in diabetes and RAGE, we tested the hypothesis that RAGE contributes to impaired regression by suppression of reverse transmigration of macrophages in an AGE-enriched environment. We evaluated if the expression of RAGE modulates influx and/or egress of macrophages from the atherosclerotic lesions in the non-diabetic and diabetic states. We used a monocyte bead-tracking model in an aorta transplantation study with LDL-/-diabetic mice fed high-fat diet as a baseline (donors), and non-diabetic RAGE-/- or WT mice as recipient. Migration patterns evaluated by labeled monocytes showed a decrease in bead number in RAGE null recipients (23±0.05p<0.05) compared to WT (30±0.05p<0.05) indicating that monocyte-derived cell content in the diabetic state was lower in the absence of RAGE. In our surgical aorta transplant model, we also examined the morphologic changes in plaques found in RAGE-/- or WT recipient mice. After lipid normalization into RAGE-/- recipient mice we observed reduced plaque cells positive for macrophage marker CD68+ (-58%), but increased plaque collagen (+51%), compared to WT recipients. Our data indicate Oil Red O stains for fatty deposit in plaque suggest a decrease (-53%) in plaque area stained and lower AGEs staining (-22%) in RAGE-/- recipient mice compared to WT recipient. Therefore, the presence of RAGE hindered plaque regression in our atherosclerotic mouse model.
We performed our studies in vitro, a reverse transmigration assay, using primary murine aortic endothelial cells from wild-type C57BL6 mice and wild-type or RAGE deficient bone marrow derived macrophages. Our data show RAGE-AGEs impact macrophage-endothelial transmigration. Our studies suggest RAGE-AGEs action delays reverse transmigration of macrophages and augments pro-inflammatory gene expression. Therefore blockade of RAGE may be able to limit pathological acceleration of vascular diseases.
Author Disclosures: L.M. Senatus: None. X. Shen: None. H. Li: None. G. Daffu: None. R. Rosario: None. A. Schmidt: None.
- © 2014 by American Heart Association, Inc.