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(Circulation. 2006;113:1226-1234.)
© 2006 American Heart Association, Inc.

Molecular Cardiology

Receptor for Advanced-Glycation End Products

Key Modulator of Myocardial Ischemic Injury

Loredana G. Bucciarelli, MD; Michiyo Kaneko, PhD; Radha Ananthakrishnan, PhD; Evis Harja, MD; Larisse K. Lee, MD; Yuying C. Hwang, PhD; Shulamit Lerner, MD; Soliman Bakr, MSc; Qing Li, PhD; Yan Lu, MD; Fei Song, DDS; Wu Qu, MD; Teodoro Gomez; Yu Shan Zou, MS; Shi Fang Yan, MD; Ann Marie Schmidt, MD; Ravichandran Ramasamy, PhD

From the Division of Surgical Science, Department of Surgery, Columbia University Medical Center, New York, NY.

Correspondence to Dr Ravichandran Ramasamy, Department of Surgery, Columbia University Medical Center, 630 W 168 St, Black Building 1706, New York, NY 10032. E-mail rr260{at}columbia.edu

Received July 14, 2005; revision received December 19, 2005; accepted December 23, 2005.

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.

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