Elsevier

Atherosclerosis

Volume 196, Issue 1, January 2008, Pages 9-21
Atherosclerosis

Review
Receptor for advanced glycation endproducts and atherosclerosis: From basic mechanisms to clinical implications

https://doi.org/10.1016/j.atherosclerosis.2007.07.025Get rights and content

Abstract

The receptor for advanced glycation endproducts (RAGE) is a member of the immunoglobulin superfamily of cell-surface molecules with a diverse repertoire of ligands. In the atherosclerotic milieu, three classes of RAGE ligands, i.e., products of non-enzymatic glycoxidation, S100 proteins and amphoterin, appear to drive receptor-mediated cellular activation and potentially, acceleration of vascular disease.

The interaction of RAGE–ligands effectively modulates several steps of atherogenesis, triggering an inflammatory-proliferative process and furthermore, critically contributing to propagation of vascular perturbation, mainly in diabetes. RAGE has a circulating truncated variant isoform, soluble RAGE (sRAGE), corresponding to its extracellular domain only. By competing with cell-surface RAGE for ligand binding, sRAGE may contribute to the removal/neutralization of circulating ligands thus functioning as a decoy. The critical role of RAGE in the chronic vascular inflammation processes highlights this receptor–ligand axis as a possible and attractive candidate for therapeutic intervention to limit vascular damage and its associated clinical disorders.

Introduction

The receptor for advanced glycation endproducts (RAGE) is a multiligand member of the immunoglobulin superfamily of cell-surface molecules, that was first described as receptor for adducts modified by non-enzymatic glycosylation occurring on proteins and lipids in a wide variety of setting, mainly in diabetes [1], [2]. The ability of RAGE to recognize a wide-range of endogenous ligands, such as advanced glycation endproducts (AGEs), S100 proteins, amphoterin and others [3], [4], [5], [6], [7], [8], suggests that this receptor may function as an excellent sensor for the environmental signals and hence play a crucial role in the regulation of homeostasis and pathogenesis. This review focuses on the pathogenetic role of RAGE–ligand interaction and its implication in the development and progression of atherosclerosis, principally in diabetes.

Chronic inflammation provides the basis for many complex diseases including atherosclerosis [9], [10]. The expression of adhesion molecules on endothelial cell surface is an early, and necessary, step in the pathogenesis of atherosclerosis [11]. In response to signals generated within the early lesion, monocytes adhere via adhesion molecules to the endothelium and then migrate into the intima by producing enzymes, including locally activated matrix metalloproteinases (MMPs) that degrade the connective tissue matrix. The activation of monocyte leads to local release of monocyte-colony stimulating factor, which causes monocytic proliferation, and cytokine-mediated progression of atherosclerosis. Attraction of inflammatory cells such as monocytes, polymorphonuclear leukocytes, and T-lymphocytes into the vessel wall offers a mechanism to protract the inflammatory response. Smooth muscle cells (SMC) are other important actors in the pathogenesis of atherosclerosis. During plaque formation SMC migrate from the media toward the intima, where they proliferate and undergo phenotypic changes. The impact of the mediators released by inflammatory cells and SMC is various and includes mitogenesis, angiogenesis, and foam cell development.

In the context of RAGE, that is expressed in all cell types relevant to the development of atherosclerotic plaque (i.e., endothelial cells, SMC, monocytes/macrophages, and lymphocytes) [12], [13], activated inflammatory cells may release mediators/RAGE–ligands such as S100 proteins and amphoterin. Once these molecules are released into the vessel wall, S100 proteins/amphoterin–RAGE interaction may amplify tissue inflammation and injury by autocrine and paracrine pathways [6].

Enhanced RAGE expression in human diabetic atherosclerotic plaques colocalize with cyclooxygenase-2 (COX-2), type 1/type 2 microsomal Prostaglandin E2, and MMPs, particularly in macrophages at the vulnerable regions of the atherosclerotic plaques [13]. The overlapping accumulation and expression of RAGE and its ligands at sites of tissue lesions sustains a RAGE-mediated cellular activation and propagation of inflammation in this established disease. Although the RAGE–ligand axis provide an important role to accelerated atherosclerosis in diabetes, several recent evidences highlight that it may contribute to chronic and amplified inflammatory status in atherosclerotic processes also beyond diabetes.

Section snippets

RAGE variants

RAGE is highly conserved across species and expressed in a wide variety of tissues: it is most abundant in the heart, lung, and skeletal muscle [2]. In the vessel wall, the RAGE is localized in the endothelium, SMC, monocytes [14], [15]. RAGE is an approximately 45-kDa protein originally isolated from bovine lung endothelium on the basis of its ability to bind AGE ligands [1]. Subsequent molecular cloning revealed RAGE as a newly identified member of the immunoglobulin superfamily of

The vascular ligands of RAGE

The RAGE is a receptor that may be activated by several proinflammatory ligands, of which those implicated in the atherosclerotic process are AGEs, S100 proteins, and amphoterin [3], [6], [32].

AGEs are complex, heterogenous molecules generated by glycation and oxidation in vivo. Protein glycation (also known as the Maillard reaction) occurs between reducing sugars and free amino-groups of a protein via nucleophilic addition that forms a Schiff base. The labile Schiff base rearranges to form a

Cellular effects of RAGE–ligand interaction

The most important pathological consequence of RAGE engagement with its ligands appears to be cellular activation, leading to the induction of oxidative stress and a broad spectrum of signalling mechanisms. The RAGE–ligand interactions lead to prolonged inflammation, mainly as a result of RAGE-dependent expression of proinflammatory cytokines and chemokines. In the vasculature, the first pathological consequence of RAGE interaction with its ligands is the induction of increased intracellular

RAGE–ligand axis: lessons from animal models

In the last decade several animal models have been developed to dissect the contribution of RAGE–ligand interaction especially in the pathogenesis of diabetic vasculopathy. The impact of RAGE blockade (through the administration of the decoy protein sRAGE or anti-RAGE IgG) was first tested in an acute animal model of diabetes-associated hyperpermeability [94]. After 9–11 weeks, rats rendered diabetic with streptozotocin showed increased vascular permeability in multiple organs that was

sRAGE: which role in the vascular disease?

RAGE expression, as above described, increases in clinical settings characterized by enhanced cell activation and prolonged exposure of RAGE ligands and it determines a chronic state of cell activation [48], [100], [101]. Interference with the vicious cycle established by RAGE–ligand interaction might interrupt cellular activation and consequently lead to an improvement of various chronic disorders [4], [7], [25]. As above mentioned, treatment with sRAGE dose-dependently suppresses the

Conclusions and perspectives

The RAGE–ligand axis is a possible common etiological factor that contributes to multiple inflammation-based chronic diseases and could represent the relationship between environmental signal-induced inflammation and atherogenetic process. The biology of RAGE has extended beyond the original notion of a receptor for glycosylated proteins. The experimental evidence gathered thus far demonstrates unequivocally that ligand–RAGE interaction can alter vessel wall homeostasis in a proatherogenic

Acknowledgements

The author thanks Nando Natale and Brunella Orlandi for their assistance in editing of English language.

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