The role of advanced glycation end-products in the development of coronary artery disease in patients with and without diabetes mellitus: a review

Abstract

Background: Traditional risk factors are insufficient to explain all cases of coronary artery disease (CAD) in patients with diabetes mellitus (DM). Advanced glycation end-products (AGEs) and their receptors may play important roles in the development and progression of CAD. BODY: Hyperglycemia is the hallmark feature of DM. An increase in the incidence of both micro-and macrovascular complications of diabetes has been observed with increased duration of hyperglycemia. This association persists even after glycemic control has been achieved, suggesting an innate mechanism of "metabolic memory." AGEs are glycated proteins that may serve as mediators of metabolic memory due to their increased production in the setting of hyperglycemia and generally slow turnover. Elevated AGE levels can lead to abnormal cross linking of extracellular and intracellular proteins disrupting their normal structure and function. Furthermore, activation of AGE receptors can induce complex signaling pathways leading to increased inflammation, oxidative stress, enhanced calcium deposition, and increased vascular smooth muscle apoptosis, contributing to the development of atherosclerosis. Through these mechanisms, AGEs may be important mediators of the development of CAD. However, clinical studies regarding the role of AGEs and their receptors in advancing CAD are limited, with contradictory results.

Conclusion: AGEs and their receptors may be useful biomarkers for the presence and severity of CAD. Further studies are needed to evaluate the utility of circulating and tissue AGE levels in identifying asymptomatic patients at risk for CAD or to identify patients who may benefit from invasive intervention.

Keywords: Advanced glycation end-products (AGEs); Coronary artery disease (CAD); Diabetes mellitus (DM); Receptor for advanced glycation end-products (RAGE).

Fig. 1

Major RAGE isoforms. The full length receptor includes one cytoplasmic domain involved in signal transduction, and three extracellular domains comprised of two c-type domains and one v-type domain. The N-truncated isoform lacks AGE binding properties and is not activated by ligand binding. Dominant negative RAGE serves as a cell-bound decoy receptor. It lacks a cytosolic domain and is not involved in signal transduction. Soluble RAGE consists of the complete extracellular domain, produced either via alternative splicing and directly secreted from the cell, or as a by-product of cleavage of full length RAGE by extracellular proteases. Copied with permission from Lee EJ, Park JH, Genomics and Informatics 2013

Fig. 2

AGE signaling cascade implicated in the development of CAD. Both endogenous and exogenously derived AGEs are involved in a cycle of formation and degradation. AGEs are recognized by two different classes of receptors which either activate or suppress the generation of reactive oxidative species. Oxidative stress leads to activation of NFκβ with multiple effects on vessel function which contribute to the development of CAD