title: RAGE modulates myocardial injury consequent to LAD infarction via impact on JNK and STAT signaling in a murine model.
abstract: The receptor for advanced glycation end-products (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 of occlusion of the LAD followed by reperfusion. At 48 h of reperfusion, hematoxylin and eosin staining revealed significantly larger infarct size in wild-type versus RAGE(-/-) mice. Contractile function, as evaluated by echocardiography 48 h after reperfusion, revealed that fractional shortening was significantly higher in RAGE(-/-) versus wild-type mice. Plasma levels of creatine kinase were markedly decreased in RAGE(-/-) versus 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. Experiments investigating the impact of RAGE on early signaling pathways influencing myocardial ischemic injury revealed attenuation of JNK and STAT5 phosphorylation in RAGE(-/-) mouse hearts versus robust activation observed in wild-type mice upon ischemia and reperfusion. Solidifying the link to RAGE, these experiments revealed that infarction stimulated the rapid production of advanced glycation end-products in the heart. Thus, we tested the effect of ligand decoy soluble RAGE (sRAGE). Administration of sRAGE protected the myocardium from ischemic damage, similar to the effects observed in RAGE(-/-) mouse 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.
authors.affiliation: Department of Surgery, Columbia University, New York, NY 10032, USA.
authors.forename: Alexey
authors.initials: A
authors.lastname: Aleshin
authors.forename: Radha
authors.initials: R
authors.lastname: Ananthakrishnan
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.forename: Rosa
authors.initials: R
authors.lastname: Rosario
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.forename: Wu
authors.initials: W
authors.lastname: Qu
authors.forename: Fei
authors.initials: F
authors.lastname: Song
authors.forename: Soliman
authors.initials: S
authors.lastname: Bakr
authors.forename: Matthias
authors.initials: M
authors.lastname: Szabolcs
authors.forename: Vivette
authors.initials: V
authors.lastname: D'Agati
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.forename: Shunichi
authors.initials: S
authors.lastname: Homma
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Schmidt
authors.forename: Shi Fang
authors.initials: SF
authors.lastname: Yan
authors.forename: Ravichandran
authors.initials: R
authors.lastname: Ramasamy
mesh_terms: D000818:Animals; D017209:Apoptosis; D003331:Coronary Vessels / Q000601:surgery; D052279:Creatine Kinase, MB Form / Q000097:blood; D004195:Disease Models, Animal; D004789:Enzyme Activation; D017127:Glycation End Products, Advanced / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008024:Ligands; D008026:Ligation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D017127:Glycation End Products, Advanced; D008024:Ligands; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D050799:STAT5 Transcription Factor; D048031:JNK Mitogen-Activated Protein Kinases; D052279:Creatine Kinase, MB Form