Receptor for Advanced Glycation End Products (RAGE) and Mechanisms and Therapeutic Opportunities in Diabetes and Cardiovascular Disease: Insights From Human Subjects and Animal Models

Abstract

Obesity and diabetes are leading causes of cardiovascular morbidity and mortality. Although extensive strides have been made in the treatments for non-diabetic atherosclerosis and its complications, for patients with diabetes, these therapies provide less benefit for protection from cardiovascular disease (CVD). These considerations spur the concept that diabetes-specific, disease-modifying therapies are essential to identify, especially as the epidemics of obesity and diabetes continue to expand. Hence, as hyperglycemia is a defining feature of diabetes, it is logical to probe the impact of the specific consequences of hyperglycemia on the vessel wall, immune cell perturbation, and endothelial dysfunction-all harbingers to the development of CVD. In this context, high levels of blood glucose stimulate the formation of the irreversible advanced glycation end products, the products of non-enzymatic glycation and oxidation of proteins and lipids. AGEs accumulate in diabetic circulation and tissues and the interaction of AGEs with their chief cellular receptor, receptor for AGE or RAGE, contributes to vascular and immune cell perturbation. The cytoplasmic domain of RAGE lacks endogenous kinase activity; the discovery that this intracellular domain of RAGE binds to the formin, DIAPH1, and that DIAPH1 is essential for RAGE ligand-mediated signal transduction, identifies the specific cellular means by which RAGE functions and highlights a new target for therapeutic interruption of RAGE signaling. In human subjects, prominent signals for RAGE activity include the presence and levels of two forms of soluble RAGE, sRAGE, and endogenous secretory (es) RAGE. Further, genetic studies have revealed single nucleotide polymorphisms (SNPs) of the AGER gene (AGER is the gene encoding RAGE) and DIAPH1, which display associations with CVD. This Review presents current knowledge regarding the roles for RAGE and DIAPH1 in the causes and consequences of diabetes, from obesity to CVD. Studies both from human subjects and animal models are presented to highlight the breadth of evidence linking RAGE and DIAPH1 to the cardiovascular consequences of these metabolic disorders.

Keywords: DIAPH1; RAGE; cardiovascular disease; diabetes; obesity; peripheral arterial disease.

Figure 1

RAGE binds DIAPH1: effect of a small molecule antagonist. Both DIAPH1 and a small molecule RAGE antagonist bind to the proximal sites on the RAGE cytoplasmic domain, suggesting a mechanism of RAGE inhibition. Interaction surfaces of DIAPH1-RAGE [see (23)] (A) and small molecule RAGE antagonist-RAGE [see (124)] (B) are mapped onto a solution structure of RAGE cytoplasmic domain (PDB code 2lmb). Affected residues are labeled. The residues are numbered based on the full length RAGE.

Figure 2

Schematic representation of the ligand-RAGE-DIAPH1 axis and its role in diabetic cardiometabolic complications. The receptor for advanced glycation end products (RAGE; gene name is AGER) mainly acts through its known ligands, such as AGEs, HMGB1, S100 family of proteins, LPA, and Aβ, which bind the RAGE extracellular domains. The cytoplasmic domain of RAGE interacts with its cytoplasmic effector protein, Diaphanous1 (DIAPH1), thereby activating multiple downstream regulators and stress responses, as illustrated in the figure. Cellular stressors such as inflammation, oxidative stress, endothelial dysfunction, and necrosis amongst others, are well-known induce cardiovascular and metabolic complications such as atherosclerosis, vascular calcification, peripheral artery disease, atrial fibrillation, thrombotic disorders, myocardial infarction, and obesity. In contrast, soluble forms of RAGE, including sRAGE, that results from cell surface-cleavage of the full-length receptor by Matrix Metallopeptidase-9 (MMP9) and A Disintegrin And Metalloproteinase Domain-Containing Protein-10 (ADAM10), and esRAGE, a product of a splice variant of AGER, have been demonstrated to show a protective role in cardiometabolic complications, at least in part, by preventing the RAGE ligands from binding to the cell surface receptor, and, therefore, reducing the RAGE-DIAPH1 signaling activation. Hence, currently identified potential therapeutic targets include blocking the binding of the ligands to the receptor and by interruption of the RAGE-DIAPH1 interaction.