The RAGE axis: a fundamental mechanism signaling danger to the vulnerable vasculature

Abstract

The immunoglobulin superfamily molecule RAGE (receptor for advanced glycation end product) transduces the effects of multiple ligands, including AGEs (advanced glycation end products), advanced oxidation protein products, S100/calgranulins, high-mobility group box-1, amyloid-beta peptide, and beta-sheet fibrils. In diabetes, hyperglycemia likely stimulates the initial burst of production of ligands that interact with RAGE and activate signaling mechanisms. Consequently, increased generation of proinflammatory and prothrombotic molecules and reactive oxygen species trigger further cycles of oxidative stress via RAGE, thus setting the stage for augmented damage to diabetic tissues in the face of further insults. Many of the ligand families of RAGE have been identified in atherosclerotic plaques and in the infarcted heart. Together with increased expression of RAGE in diabetic settings, we propose that release and accumulation of RAGE ligands contribute to exaggerated cellular damage. Stopping the vicious cycle of AGE-RAGE and RAGE axis signaling in the vulnerable heart and great vessels may be essential in controlling and preventing the consequences of diabetes.

Figure 1. Glucose – igniting mechanisms leading to accelerated atherosclerosis and myocardial infarction: inciting RAGE in diabetes

Central to diabetes is the development of hyperglycemia. We predict that very early in glucose intolerance or diabetes, elevated levels of glucose surpass a threshold; once beyond that threshold, AGEs accumulate (I) and stimulate RAGE. One consequence of RAGE signaling is the activation of NADPH oxidase (II) and production of ROS (III). Increased ROS may then contribute to increased production of AOPPs, more AGEs and AGE-modification of oxLDLs. Furthermore, increased ROS may deplete glutathione, thereby suppressing glyoxalase I activity – a mechanism favoring even further AGE accumulation (IV). AGEs, AOPPS, AGE-oxLDL ligands of RAGE sustain stimulation of RAGE and these processes, together with increased ROS, activate key transcription factors such as NF-kB and Egr-1 (V) which activate fundamental inflammatory mechanisms (VI). Consequences include increased migration and activation of RAGE-expressing neutrophils, monocytes/macrophages, T cells, and dendritic cells (VII). This results in release of the pro-inflammatory RAGE ligands S100/calgranulins and HMGB1. In this inflammatory environment, further AGEs may be formed as well. Via interaction with RAGE, these ligands magnify activation of NF-kB, Egr-1 and other factors (VIII), thereby amplifying cellular stress and tissue damage. In the aggregate, these processes may lead to accelerated atherosclerosis and increased myocardial damage in diabetes. Stopping the vicious cycle of RAGE ligand-RAGE interaction will be essential in curbing the maladaptive effects of glucose in diabetes.