Receptor for Advanced-Glycation End Products

Abstract

Background-The beneficial effects of reperfusion therapies have been limited by the amount of ischemic damage that occurs before reperfusion. To enable development of interventions to reduce cell injury, our research has focused on understanding mechanisms involved in cardiac cell death after ischemia/reperfusion (I/R) injury. In this context, our laboratory has been investigating the role of the receptor for advanced-glycation end products (RAGE) in myocardial I/R injury. Methods and Results-In this study we tested the hypothesis that RAGE is a key modulator of I/R injury in the myocardium. In ischemic rat hearts, expression of RAGE and its ligands was significantly enhanced. Pretreatment of rats with sRAGE, a decoy soluble part of RAGE receptor, reduced ischemic injury and improved functional recovery of myocardium. To specifically dissect the impact of RAGE, hearts from homozygous RAGE-null mice were isolated, perfused, and subjected to I/R. RAGE-null mice were strikingly protected from the adverse impact of I/R injury in the heart, as indicated by decreased release of LDH, improved functional recovery, and increased adenosine triphosphate (ATP). In rats and mice, activation of the RAGE axis was associated with increases in inducible nitric oxide synthase expression and levels of nitric oxide, cyclic guanosine monophosphate (cGMP), and nitrotyrosine. Conclusions-These findings demonstrate novel and key roles for RAGE in I/R injury in the heart. The findings also demonstrate that the interaction of RAGE with advanced-glycation end products affects myocardial energy metabolism and function during I/R. (Circulation. 2006;113:1226-1234.)

RAGE Does Not Contribute to Renal Injury and Damage upon Ischemia/Reperfusion-Induced Injury

“…In line with these results, we showed RAGE expression on podocyte and tubuli but also on cells of the collecting duct. Earlier studies have shown that RAGE expression was increased in heart, brain and liver following I/R injury [8,12,[24][25][26] . We showed that RAGE expression in the kidney is unaltered early after I/R but is decreased 5 days after I/R.…”

Green Tea Catechin Polyphenols Attenuate Behavioral and Oxidative Responses to Intermittent Hypoxia

“…Advanced glycation end products (AGEs) resulting from nonenzymatic glycation of proteins and lipids accumulate during normal aging and at an accelerated rate in age-related disorders such as diabetes mellitus and atherosclerosis (49,50). The interaction of AGEs with their main receptor, RAGE, induces intracellular generation of reactive oxygen species and up-regulation of inflammatory pathways dependent on RAGE signal transduction (51, 52).…”

Perspectives on RAGE signaling and its role in cardiovascular disease

“…For example, RAGE and its ligands in experimental atherosclerosis have been halted and reversed by using soluble RAGE [Lindsey et al, 2009]. Another example is the pharmacological blockage of RAGE ischemia-reperfusion injury to the heart, resulting in protection of the injured heart from further damage and also improving its function [Bucciarelli et al, 2006[Bucciarelli et al, , 2008.…”

“…In mice treated with recombinant HMGB1, increased injury to the heart occurs, but by treating them with HMGB1 Box A, which is antagonistic to HMGB1, protects them against ischemia-hyperperfusion to a significant degree [Andrassy et al, 2008]. Bucciarelli et al [2006] reported two studies of RAGE ischemiahyperperfusion heart injury. They indicated that RAGE signaling produces myocardial injury by the direct action of high glucose as well as by the interaction of nitric oxide and superoxide, likely resulting in perioxynitrite, which is a longer-lived oxidant, whose impact is diverse and deleterious.…”

“…In a rat study, they used sRAGE as a decoy receptor, which reduced the ischemic injury and improved the functional recovery of the heart. In a study of RAGE-null mice À/À , they were protected from ischemia-hyperperfusion heart injury with improved functional recovery indicated by decreased lactate dehydrogenase (LDH) and increased adenosine triphosphate (ATP) [Bucciarelli et al, 2006]. Bucciarelli et al [2008] also studied RAGE signaling in rodent models of type 1 diabetes.…”