Advanced Glycation End Products Activate Endothelium Through Signal-Transduction Receptor RAGE

Abstract

Background-The products of nonenzymatic glycation and oxidation of proteins, the advanced glycation end products (AGEs), form under diverse circumstances such as aging, diabetes, and kidney failure. Recent studies suggested that AGEs may form in inflamed foci, driven by oxidation or the myeloperoxidase pathway. A principal means by which AGEs alter cellular properties is through interaction with their signal-transduction receptor RAGE. We tested the hypothesis that interaction of AGEs with RAGE on endothelial cells enhances vascular activation.

Glycolaldehyde-derived advanced glycation end products (glycol-AGEs)-induced vascular smooth muscle cell dysfunction is regulated by the AGES-receptor (RAGE) axis in endothelium

“…The AGEs-RAGE interaction raises the permeability of ECs and promotes the invasion of molecules through the EC barrier (Basta et al 2002). The AGEs-RAGE axis may induce intracellular ROS formation, stimulating NADPH oxidase (Wautier et al 2001).…”

Levels of soluble receptor for AGE are cross-sectionally associated with cardiovascular disease in type 1 diabetes, and this association is partially mediated by endothelial and renal dysfunction and by low-grade inflammation: the EURODIAB Prospective Complications Study

“…The current view is that the activation of RAGE, a 55 kDa protein and member of the immunoglobulin superfamily of cell-surface receptors, through ligand binding activates the endothelial cell and triggers multiple signalling cascades [8,9]. This results in activation and translocation of nuclear transcription factors and transcription of the target genes, including those for VCAM-1 [9], E-selectin [10] and proinflammatory cytokines [11]. AGEs are positive regulators of the cellular RAGE expression [46], and an increased formation of AGEs enhanced the expression and secretion of the soluble forms of RAGE [47,48].…”

“…The functional role of these soluble forms of RAGE in the circulation remains unclear, but they may reflect the activity of the AGE-RAGE axis. The ligation of RAGE activates the endothelial cell and triggers multiple signalling cascades [8,9], resulting in activation and translocation of nuclear transcription factors and transcription of the target genes, including adhesion molecules [9,10] and proinflammatory cytokines [11]. The activation of RAGE may also lead to nephropathy [12].…”

The Mechanisms of Inhibition of Advanced Glycation End Products Formation through Polyphenols in Hyperglycemic Condition

“…Another effect of AGEs on the induction of atherosclerosis is related to interaction of AGEs with RAGE on the cell surface. AGE-RAGE complex induces atherosclerosis through enhancement of the expression of VCAM-1 on endothelial cells [22]. VCAM-1 facilitates the adhesion of mononuclear proinflammatory cells, and the activation of NADPH oxidase, which finally accelerates migration of lymphocytes from stimulated cells [23].…”