RAGE and Modulation of Ischemic Injury in the Diabetic Myocardium

Abstract

OBJECTIVE-Subjects with diabetes experience an increased risk of myocardial infarction and cardiac failure compared with nondiabetic age-matched individuals. The receptor for advanced glycation end products (RAGE) is upregulated in diabetic tissues.In this study, we tested the hypothesis that RAGE affected ischemia/reperfusion (I/R) injury in the diabetic myocardium. In diabetic rat hearts, expression of RAGE and its ligands was enhanced and localized particularly to both endothelial cells and mononuclear phagocytes.RESEARCH DESIGN AND METHODS-To specifically dissect the impact of RAGE, homozygous RAGE-null mice and transgenic (Tg) mice expressing cytoplasmic domain-deleted RAGE (DN RAGE), in which RAGE-dependent signal transduction was deficient in endothelial cells or mononuclear phagocytes, were rendered diabetic with streptozotocin. Isolated perfused hearts were subjected to I/R. RESULTS-Diabetic RAGE-null mice were significantly protected from the adverse impact of I/R injury in the heart, as indicated by decreased release of LDH and lower glycoxidation products carboxymethyl-lysine (CML) and pentosidine, improved functional recovery, and increased ATP. In diabetic Tg mice expressing DN RAGE in endothelial cells or mononuclear phagocytes, markers of ischemic injury and CML were significantly reduced, and levels of ATP were increased in heart tissue compared with littermate diabetic controls. Furthermore, key markers of apoptosis, caspase-3 activity and cytochrome c release, were reduced in the hearts of diabetic RAGE-modified mice compared with wild-type diabetic littermates in I/R.CONCLUSIONS-These findings demonstrate novel and key roles for RAGE in I/R injury in the diabetic heart. Diabetes 57: [1941][1942][1943][1944][1945][1946][1947][1948][1949][1950][1951] 2008 C ardiac complications remain a leading cause of morbidity and mortality in subjects with diabetes (1-3). Although many factors contribute to depressed cardiac function in diabetes, innate disturbances within the diabetic heart contribute importantly to progressive dysfunction, which often leads to irreversible failure and death (3). Alterations in substrate metabolism and increased levels of oxygen free radicals have been observed in diabetic tissues. Inflammatory cytokines may exert direct negative inotropic effects on cardiac myocytes and contribute to aberrant remodeling in the failed heart (4 -8). The pathophysiology of diabetesassociated cardiac complications is complex and involves a host of factors linked to metabolic and immune/inflammatory cell activation.The accumulation of late-stage glycoxidation adducts of proteins, termed advanced glycation end products (AGEs), occurs in diabetic tissues. AGEs modify long-lived molecules in the blood vessel wall and structural tissues of the heart considerably earlier than symptomatic cardiac dysfunction occurs (9). A major way in which AGEs exert their cellular effects is by ligation of the multiligand receptor for AGE (RAGE) (10 -13).We tested the role of RAGE in rodent models of type 1 dia...

Inflammatory stress in primary venous and aortic endothelial cells of type 1 diabetic mice

“…For example, in diabetic hearts in ischaemia and/or reperfusion injury, increased apoptosis ensues, as indicated by cytochrome c release and activation of caspase-3. 21,22 In our studies, an apparently paradoxical observation was that Birc2 was significantly upregulated in aortic EC in short-term diabetes, and was highly upregulated in both aortic and venous EC in long-term diabetes. Birc2 is implicated in anti-apoptotic mechanisms and therefore maintenance of vessel integrity and survival.…”

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 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. They demonstrated that that by blocking RAGE ligands or by genetic modulation of RAGE itself, ischemiareperfusion injury was suppressed in the heart at least in part by RAGE-expressed endothelial cells and mononuclear phagocytes in the diabetic heart.…”

Stopping the Primal RAGE Reaction in Myocardial Infarction

“…Experiments with the soluble ligand-binding decoy of RAGE, soluble or sRAGE, supported that binding up RAGE ligands and blocking their access to the cell surface receptor imparted cardioprotection. [2][3][4] In this context, a question that arises is, if multiple ligands of RAGE are potentially involved in I/R injury in the heart, then why did HMGB1 blockade alone exert such a potent effect in the studies of Andrassy and colleagues? Previous findings indicated that the ligands of the receptor cross compete with each other in ligand-binding assays, 8 and recent insights suggest that perhaps multimeric higher-order structures of these ligands may indeed be the key species interacting with the RAGE extracellular domain.…”

“…[1][2][3][4] A major cause of injury, especially in the reperfusion phase, is the influx of inflammatory cells into the stressed heart. Andrassy and colleagues show that infiltrating leukocytes express proinflammatory HMGB1 and that HMGB1 plays fundamental roles in injury responses in the I/R heart.…”