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1 New York, New York, United States; Surgery, Columbia University Medical Center, New York, New York, United States
2 Surgery, Columbia University Medical Center, New York, New York, United States
3 Department of Surgery, Columbia University, Columbia, New York, United States
4 Pathology, Columbia University Medical Center, New York, New York, United States
5 United States; Pathology, Columbia University Medical Center, New York, New York, United States
6 Department of Surgery, Columbia University College of Physicians and Surgeons, New York, New York, United States
7 Medicine, Columbia University Medical Center, NY, New York, United States
8 New York, New York, United States; Medicine, Columbia University Medical Center, NY, New York, United States
9 Columbia University, 630 West 168 Street, New York, New York, 10032, United States; Surgery, Columbia University Medical Center, New York, New York, United States
* To whom correspondence should be addressed. E-mail: rr260{at}columbia.edu.
The Receptor for Advanced Glycation Endproducts (RAGE) has been implicated in the pathogenesis of ischemia-reperfusion (I/R) injury in the isolated perfused heart. To test the hypothesis that RAGE-dependent mechanisms modulated responses to I/R in a murine model of transient occlusion and reperfusion of the left anterior descending coronary artery (LAD), we subjected male homozygous RAGE-/- mice and their wild-type age-matched littermates to 30 min occlusion of the LAD coronary artery followed by reperfusion. At 48 hrs reperfusion, hematoxylin and eosin staining revealed significantly larger infarct size in wild type mice vs. RAGE-/-mice. Contractile function evaluated by echocardiography 48hr after reperfusion revealed that fractional shortening (FS) was significantly higher in RAGE-/- vs. wild-type mice. Plasma levels of Creatine kinase were markedly decreased in RAGE-/- mice vs. wild type animals. Integral to the impact of RAGE deletion on diminished myocardial damage after infarction was significantly decreased apoptosis in the heart, as assessed by TUNEL staining, release of cytochrome C, and caspase-3 activity. Studies investigating the impact of RAGE on early signaling pathways influencing myocardial ischemic injury revealed attenuation of JNK and STAT5 phosphorylation in RAGE-/- mice hearts vs. robust activation observed in wild type mice upon ischemia and reperfusion. Solidifying the link to RAGE, these experiments revealed that infarction stimulated rapid production of AGEs in the heart. Thus, we tested the effect of the ligand decoy soluble or sRAGE. Administration of sRAGE protected the myocardium from ischemic damage, similar to the effects observed in RAGE-/- mice hearts. Taken together, these data implicate RAGE and its ligands in the pathogenesis of I/R injury and identify JNK and STAT signal transduction as central downstream effector pathways of the ligand-RAGE axis in the heart subjected to I/R injury.
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