22016 ATVB Plenary Lecture: Receptor for Advanced Glycation Endproducts and Implications for the Pathogenesis and Treatment of Cardiometabolic Disorders: Spotlight on the Macrophage.
The receptor for advanced glycation endproducts (RAGE) interacts with a unique repertoire of ligands that form and collect in the tissues and circulation in diabetes mellitus, aging, inflammation, renal failure, and obesity. RAGE is expressed on multiple cell types linked to tissue perturbation in these settings. This brief review focuses on the role of RAGE in monocytes/macrophages and how RAGE ligand engagement on these cells mediates seminal changes in monocyte/macrophage migration, oxidative stress, cholesterol efflux, and pro- versus anti-inflammatory cues that signal to tissue damage. Studies using mice devoid ofAger(gene encoding RAGE) or pharmacological antagonists of RAGE are protective in animal models of diabetes mellitus, atherosclerosis, and high-fat diet-induced obesity, in least in part through key roles in monocytes/macrophages. RAGE signal transduction requires the interaction of RAGE cytoplasmic domain with the formin, DIAPH1 (diaphanous 1) and novel antagonists of this interaction show significant promise in attenuation of the maladaptive effects of RAGE ligands in cellular and in vivo models. Finally, this brief review discusses evidence for RAGE axis perturbation in human monocytes/macrophages and how tracing RAGE activity in these cells may identify target engagement biomarkers of RAGE antagonism for future clinical trials.
From the Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University School of Medicine, New York. annmarie.schmidt@nyumc.org.
Ann Marie
AM
Schmidt
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D050197:Atherosclerosis / Q000188:drug therapy / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D018345:Mice, Knockout; D000067759:Receptor for Advanced Glycation End Products / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
C000593871:AGER protein, human; C000593873:Ager protein, mouse; D000893:Anti-Inflammatory Agents; D008024:Ligands; D000067759:Receptor for Advanced Glycation End Products
RAGE; atherosclerosis; diabetes mellitus; inflammation; obesity