AGE–RAGE Stress and Coronary Artery Disease

Coronary artery atherosclerosis and atherosclerotic plaque rupture cause coronary artery disease (CAD). Advanced glycation end products (AGE) and its cell receptor RAGE, and soluble receptor (sRAGE) and endogenous secretory RAGE (esRAGE) may be involved in the development of atherosclerosis. AGE and its interaction with RAGE are atherogenic, while sRAGE and esRAGE have antiatherogenic effects. AGE–RAGE stress is a ratio of AGE/sRAGE. A high AGE–RAGE stress results in development and progression of CAD and vice-versa. AGE levels in serum and skin, AGE/sRAGE in patients with CAD, and expression of RAGE in animal model of atherosclerosis were higher, while serum levels of esRAGE were lower in patients with CAD compared with controls. Serum levels of sRAGE in CAD patients were contradictory, increased or decreased. This contradictory data may be due to type of patients used, because the sRAGE levels are elevated in diabetics and end-stage renal disease. AGE/sRAGE ratio is elevated in patients with reduced or elevated levels of serum sRAGE. It is to stress that AGE, RAGE, sRAGE, or esRAGE individually cannot serve as universal biomarker. AGE and sRAGE should be measured simultaneously to assess the AGE–RAGE stress. The treatment of CAD should be targeted at reduction in AGE levels, prevention of AGE formation, degradation of AGE in vivo, suppression of RAGE expression, blockade of RAGE, elevation of sRAGE, and use of antioxidants. In conclusion, AGE–RAGE stress would initiate the development and progression of atherosclerosis. Treatment modalities would prevent, regress, and slow the progression of CAD.

Divergent Changes in Plasma AGEs and sRAGE Isoforms Following an Overnight Fast in T1DM

Advanced glycation end products (AGEs) promote the development of diabetic complications through activation of their receptor (RAGE). Isoforms of soluble RAGE (sRAGE) sequester AGEs and protect against RAGE-mediated diabetic complications. We investigated the effect of an overnight fast on circulating metabolic substrates, hormones, AGEs, and sRAGE isoforms in 26 individuals with type 1 diabetes (T1DM). Blood was collected from 26 young (18–30 years) T1DM patients on insulin pumps before and after an overnight fast. Circulating AGEs were measured via LC-MS/MS and sRAGE isoforms were analyzed via ELISA. Glucose, insulin, glucagon, and eGFRcystatin-c decreased while cortisol increased following the overnight fast (p < 0.05). AGEs (CML, CEL, 3DG-H, MG-H1, and G-H1) decreased (21–58%, p < 0.0001) while total sRAGE, cleaved RAGE (cRAGE), and endogenous secretory RAGE (esRAGE) increased (22–24%, p < 0.0001) following the overnight fast. The changes in sRAGE isoforms were inversely related to MG-H1 (rho = −0.493 to −0.589, p < 0.05) and the change in esRAGE was inversely related to the change in G-H1 (rho = −0.474, p < 0.05). Multiple regression analyses revealed a 1 pg/mL increase in total sRAGE, cRAGE, or esRAGE independently predicted a 0.42–0.52 nmol/L decrease in MG-H1. Short-term energy restriction via an overnight fast resulted in increased sRAGE isoforms and may be protective against AGE accumulation.

Advanced Glycation End Products and its Soluble Receptors in the Pathogenesis of Thoracic Aortic Aneurysm

Background: Matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of thoracic aortic aneurysms (TAAs). Cytokines [Interleukin (IL)-Iβ, IL-2, IL-6, and TNF-α)] increase the expression of MMP-2 and -3. Advanced glycation end products (AGEs) interact with cell receptors to increase the release of cytokines. Circulating soluble receptors for AGEs (sRAGE) and endogenous secretory RAGE (esRAGE) compete with membrane bound RAGE for binding with AGEs and reduce the production of cytokines. It is hypothesized that low levels of serum sRAGE and esRAGE and high levels of AGEs, AGEs/sRAGE, and AGEs/esRAGE would increase the levels of cytokines that would increase the levels MMPs, thus contributing to the formation of TAAs. Methods: The study population was composed of 17 control subjects and 20 patients with TAA. Blood samples were collected for measurement of serum sRAGE, esRAGE, AGEs, cytokines, and MMPs. AGEs, sRAGE, and esRAGE were measured using ELISA kits, whereas the remaining parameters were measured using the Luminex Multi-Analyte system. Results: The levels of sRAGE were lower, while the levels of AGEs, AGEs/sRAGE, AGEs/esRAGE, cytokines and MMPs were higher in patients with TAA compared to controls. The levels of sRAGE were inversely correlated with cytokines and MMPs, while AGEs, AGEs/sRAGE and AGEs/esRAGE were positively correlated with cytokines and MMPs. Cytokines were positively correlated with MMPs. Conclusions: The data suggest that the AGE-RAGE axis may be involved in the pathogenesis of TAA and that low levels of sRAGE and high levels of AGEs, AGEs/sRAGE, and AGEs/esRAGE are risk factors for TAA.