Abstract
Receptor for advanced glycation end-products (RAGE) is known to be involved in microvascular complications in diabetes. RAGE is also profoundly associated with macrovascular complications in diabetes through regulation of atherogenesis, angiogenic response, vascular injury, and inflammatory response. The potential significance of RAGE in the pathogenesis of cardiovascular disease appears not to be confined solely to nondiabetic rather than diabetic conditions. Numerous truncated forms of RAGE have recently been described, and the C-terminally truncated soluble form of RAGE has received much attention. Soluble RAGE consists of several forms, including endogenous secretory RAGE (esRAGE), which is a spliced variant of RAGE, and a shedded form derived from cell-surface RAGE. These heterogeneous forms of soluble RAGE, which carry all of the extracellular domains but are devoid of the transmembrane and intracytoplasmic domains, bind ligands including AGEs and can antagonize RAGE signaling in vitro and in vivo. ELISA systems have been developed to measure plasma esRAGE and total soluble RAGE, and the pathophysiological roles of soluble RAGE have begun to be unveiled clinically. In this review, we summarize recent findings regarding pathophysiological roles in cardiovascular disease of RAGE and soluble RAGE and discuss their potential usefulness as therapeutic targets and biomarkers for the disease.
Highlights
Receptor for advanced glycation endproducts is a multiligand cell-surface protein that was isolated from bovine lung in 1992 by Schmidt et al and Neeper et al [1,2]
The decrease in expression of vascular endothelial growth factor (VEGF) in diabetes, was observed in Receptor for advanced glycation end-products (RAGE)-null mice (Figure 3B). This result was in good agreement with an in vitro finding that a decrease in VEGF secretion in smooth muscle cells cultured on glycated type 1 collagen was again independent of the presence of RAGE (Figure 3C). These results suggest that the RAGE-mediated decrease in angiogenic response in diabetes is not necessarily explained by regulation of proangiogenic factors such as VEGF
The association between plasma soluble RAGE (sRAGE) and atherosclerosis must be confirmed in larger studies, in diabetic subjects, but recent findings suggest that plasma endogenous secretory RAGE (esRAGE) and sRAGE may be markers for atherosclerosis and cardiovascular disease
Summary
Receptor for advanced glycation endproducts (receptor for AGEs, RAGE) is a multiligand cell-surface protein that was isolated from bovine lung in 1992 by Schmidt et al and Neeper et al [1,2]. RAGE-dependent expression of proinflammatory mediators such as monocyte chemoattractant protein 1 and vascular cell adhesion molecule-1 (VCAM-1) [13,14]. The cytosolic portion of RAGE appears to be critical in transducing the signal from the cell surface to downstream targets. RAGEANDSOLUBLERAGEINCARDIO VA SCULARDISEASE ministration of sRAGE stabilized the atherosclerotic lesion area and complexity at an advanced phase in diabetic apoE-null mice, and suppressed inflammatory markers such as expression of cyclooxygenase 2, VCAM-1, JE-monocyte chemoattractant protein 1, matrix metalloproteinase 9 activity, tissue factor, and phosphorylation of p38 MAP kinase. The role of RAGE in progression of atherosclerosis may be independent of the presence of diabetes, because sRAGE administration was found to significantly stabilize atherosclerotic lesion area and complexity in nondiabetic apoE-null mice [20]
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