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.
Highlights
We reported the discovery of the receptor for advanced glycation end products (RAGE; gene name is AGER) in 1992 on account of this molecule’s ability to bind the products of non-enzymatic glycation and oxidation of proteins/lipids, the advanced glycation end products, or AGEs [1]
The pivotal discovery in the biology of RAGE was the finding that RAGE bound a diverse series of ligands beyond AGEs, such as members of the S100/calgranulin family, highmobility group box 1 (HMGB1), lysophosphatidic acid (LPA) and oligomeric forms of amyloid beta peptide (Aβ) and islet amyloid polypeptide (IAPP) [6,7,8,9,10]
In another study examining the effects of therapeutic intervention, higher plasma levels of sRAGE were independently associated with reduced rate of recurrence of atrial fibrillation (AF) after catheter ablation in diabetic patients [77]
Summary
We reported the discovery of the receptor for advanced glycation end products (RAGE; gene name is AGER) in 1992 on account of this molecule’s ability to bind the products of non-enzymatic glycation and oxidation of proteins/lipids, the advanced glycation end products, or AGEs [1]. The patients with the highest quartile of sRAGE displayed the highest incidence of recurrent CVD events, even after correction for confounders for CVD [43] These recent studies add to a large body of reports on the relationship between sRAGEs and diabetes and CVD and suggest the following insights: [1] High levels of sRAGEs may be protective, at least in early stages of disease or, perhaps, in periods of active exacerbation of acute CVD events; and [2] even after the discernment of early metabolic vulnerability subsets in subjects without diagnosed diabetes, the levels of sRAGEs may align with markers of CVD risk. Beyond genes regulating cholesterol efflux, significant attenuation of vascular inflammation was observed upon deletion of Ager in diabetic atherosclerotic mice
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
