Role of Hyperglycemia-Induced Advanced Glycation End Product (AGE) Accumulation in Atherosclerosis

Abstract

There is a growing body of evidence that cumulative hyperglycemic exposure plays a central role in the development and progression of atherosclerotic cardiovascular disease in diabetic patients. Monosaccharides, such as glucose, fructose, and glyceraldehyde can react non-enzymatically with amino groups of proteins, lipids, nucleic acids to form senescent macromolecules termed advanced glycation end products (AGEs), whose formation and accumulation has been known to progress in diabetic patients, especially in those with a long history of disease. The sustained accumulation of AGEs could contribute to the phenomenon of metabolic memory or legacy effects observed in long-term follow-up clinical studies of diabetic patients. AGE modification alters the structural integrity and function of various types of macromolecules, and interaction of AGEs with a receptor for AGEs (RAGE) has been shown to evoke inflammatory and thrombotic reactions. Therefore, the AGE–RAGE axis is a novel therapeutic target of atherosclerotic cardiovascular disease in diabetic patients. In this paper, we briefly review the pathological role of AGEs and their receptor RAGE system in atherosclerotic cardiovascular disease, including peripheral artery disease and discuss the clinical utility of measuring AGEs in evaluating the severity of atherosclerosis in patients with diabetes.

Cellular Metabolomics Reveal the Mechanism Underlying the Anti-Atherosclerotic Effects of Aspirin Eugenol Ester on Vascular Endothelial Dysfunction

“…Excessive LDL, particularly oxidized low-density lipoproteins (ox-LDL), causes early atherosclerosis by disturbing the function of the endothelium [52,53,54]. Moreover, the formation of AGEs induced by various stimuli accelerates the development of atherosclerosis by increasing the expression of adhesion molecules [55,56,57]. In the present study, AEE reduced the increase in the serum LDL, AGE, sVCAM-1 and sE-selectin levels in HFD-fed rats and decreased VCAM-1 and E-selectin expression, which might be related to an amelioration of the excessive accumulation of LDL and AGEs in the blood vessel.…”

Toxicity of advanced glycation end products (Review)

“…Their isolation from tissues can cause undesirable chemical modifications and the formation of artefacts ( 44 ). Nevertheless, research on the content of AGEs in serum, in tissues and in food is very desirable, particularly for diagnostic and therapeutic purposes ( 14 , 21 , 38 , 41 , 45 , 46 ).…”

“…Equally popular are immunoenzymatic methods using antibodies ( 1 , 4 , 44 , 47 ); however, the specificity of the antibodies ( 11 , 14 ) or the low quantities of antigens in the sample can cause difficulties ( 1 ). The natural properties of AGEs associated with fluorescence can also be exploited in fluorometric methods ( 43 , 45 , 47 ); unfortunately, the fluorescence of other components in the sample often obfuscates the results ( 11 ). Thus, at present, there is no one specific and sensitive method to measure AGE content in samples ( 11 ).…”

Advanced glycation end products and their adverse effects: The role of autophagy

“…[119] Even reduced LDL uptake due to the glycation of apolipoprotein B100 is implicated in atherosclerosis. [120,121] AGEs/RAGE axis in endothelial cells activate various pathways with detrimental effects like ER stress, inflammation, and oxidative stress, which results in the cytoskeletal rearrangement in cells leading to their enhanced permeability. [122] Similarly, AGEs/RAGE signaling in vascular smooth muscle cells (VSMCs) activates MMP-2/9, inflammatory cytokines, and ER stress pathways resulting in proliferation and extracellular matrix degradation, along with impaired autophagy and lysosomal degradation.…”