Atherosclerosis and the Hypercholesterolemic AGE–RAGE Axis

Abstract

Reactive oxygen species (ROS) have been implicated in the initiation and the progression of hypercholesterolemia-induced atherosclerosis. 1-3 Hypercholesterolemia increases the generation of ROS through various mechanisms. 4,5 Additionally, hypercholesterolemia increases the activity of nicotinamide adenine dinucleotide phosphateoxidase (NADPH oxidase), xanthine oxidase, 6 and myeloperoxidase 7 that leads to the generation of ROS. Keywords► atherosclerosis ► advanced glycation end product ► hypercholesterolemia ► oxidative stress ► coronary artery AbstractBackground Interaction of advanced glycation end products (AGE) with the receptor for advanced glycation end products (RAGE) has been implicated in the pathogenesis of atherosclerosis. Soluble receptors for advanced glycation end products (sRAGE) act as a decoy for AGE by competing with RAGE and suppressing developing atherosclerosis. Hypercholesterolemia and the oxidative stress are known factors involved in atherosclerosis. High-density lipoprotein cholesterol (HDL-C) is known to exert a protective effect against the development of atherosclerosis. We hypothesize that hypercholesterolemia-induced atherosclerosis may be mediated through the AGE-RAGE axis. Objectives Two objectives to be determined are: (1) if hypercholesterolemia is positively correlated with serum AGE, AGE/sRAGE, and malondialdehyde (MDA: a marker for oxidative stress) and (2) if the protective effect of HDL-C is positively associated with serum sRAGE and negatively correlated with the levels of AGE and AGE/sRAGE. Methods Measurement of serum lipid levels from 100 patients allowed the separation into two groups (hypercholesterolemic and normocholesterolemic). Measurements of serum levels of AGE, sRAGE, and MDA were performed. Results Serum levels of sRAGE were lower, while the levels of AGE and AGE/sRAGE were higher in hypercholesterolemic subjects as compared with normocholesterolemic subjects. sRAGE levels are positively correlated with HDL, while they are negatively correlated with low-density lipoprotein, triglycerides, total cholesterol, and MDA in hypercholesterolemic subjects. Conclusions Hypercholesterolemia is positively correlated with serum AGE, AGE/sRAGE, and MDA. The effect of HDL-C may be due to increases in sRAGE and decreases in the levels of AGE and AGE/sRAGE. Hypercholesterolemia-induced atherosclerosis may be mediated through the AGE-RAGE axis; however, more research must be conducted.

The use of the soluble receptor for advanced glycation-end products (sRAGE) as a potential biomarker of disease risk and adverse outcomes

“…Hence, sRAGE is sometimes attributed an ‘anti-oxidant role’. This view has been also supported by reports from small clinical studies of atherosclerotic vascular disease or cardiometabolic disorders describing inverse correlations between sRAGE levels and makers of oxidative stress [ [68] , [69] , [70] , [71] , [72] , [73] ], and by a study describing a positive correlation with plasma anti-oxidant defenses in Alzheimer's disease patients [ 74 ]. However, it should be noted that these types of associations are not universal.…”

Soluble receptor for advanced glycation end products (sRAGE) as a biomarker of COPD

“…The ROC curves for sRAGE, which do not exceed 0.75 for emphysema, suggest that it should not be used as a sole diagnostic test to rule emphysema in or out, rather that it can be used as an enrichment measure to increase or decrease the probability that an individual has emphysema similar to how ventilation perfusion scintigraphy has been used. While we did adjust analyses for important covariates such as BMI, there were some covariates that were not available in most cohorts, but might affect sRAGE measurements (e.g., lipid measurements [ 44 ]). Finally, sRAGE is also lower in participants with idiopathic pulmonary fibrosis [ 45 ], suggesting that it may be a non-specific marker of loss of lung epithelium (similar to DLco), rather than a specific marker of emphysema.…”

Analysis of Oxidative Stress-Related Markers in Crohn’s Disease Patients at Surgery and Correlations with Clinical Findings

“…On the contrary, there are no reports available in the literature on the serum level of AGEs in patients with CD. AGEs are heterogeneous compounds mainly generated through the non-enzymatic glycation of protein, lipids, and nucleic acid driven by hyperglycemia and oxidative stress, but increased serum levels were associated with hypercholesterolemia [31] and cigarette smoking [32]. In addition, humans are exposed to dietary sources of AGEs through animal-derived foods and cooking processes that result in the formation of new AGEs [33].…”