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RAGE & MODULATION OF ISCHEMIC INJURY IN THE DIABETIC MYOCARDIUM

Division of Surgical Science, Department of Surgery, Columbia University Medical Center, New York, New York, 10032, USA, Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA

OBJECTIVE: Subjects with diabetes experience an increased risk of myocardial infarction and cardiac failure compared to non-diabetic age-matched individuals. The Receptor for Advanced Glycation Endproducts (RAGE) is upregulated in diabetic tissues. In this study, we tested the hypothesis that RAGE impacted on 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 (EC) and mononuclear phagocytes (MP).

RESEARCH DESIGN & METHODS: To specifically dissect the impact of RAGE, homozygous RAGE null mice and transgenic mice expressing cytoplasmic domain-deleted RAGE (or DN RAGE), in which RAGE-dependent signal transduction was deficient in EC or MP, 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 CML and pentosidine, improved functional recovery, and increased ATP. In diabetic transgenic mice expressing DN RAGE in EC or MP, markers of ischemic injury and CML were significantly reduced, and levels of ATP were increased in heart tissue compared to littermate diabetic controls. Further, key markers of apoptosis, caspase-3 activity and cytochrome c release, were reduced in the hearts of diabetic RAGE-modified mice compared to 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.

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