TY - JOUR
T1 - Receptor for advanced-glycation end products
T2 - Key modulator of myocardial ischemic injury
AU - Bucciarelli, Loredana G.
AU - Kaneko, Michiyo
AU - Ananthakrishnan, Radha
AU - Harja, Evis
AU - Lee, Larisse K.
AU - Hwang, Yuying C.
AU - Lerner, Shulamit
AU - Bakr, Soliman
AU - Li, Qing
AU - Lu, Yan
AU - Song, Fei
AU - Qu, Wu
AU - Gomez, Teodoro
AU - Yu, Shan Zou
AU - Shi, Fang Yan
AU - Schmidt, Ann Marie
AU - Ramasamy, Ravichandran
PY - 2006/3
Y1 - 2006/3
N2 - 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.
AB - 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.
KW - Advanced-glycation end products
KW - Ischemic injury
KW - Metabolism
KW - Nitric oxide synthase
KW - Receptors
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U2 - 10.1161/CIRCULATIONAHA.105.575993
DO - 10.1161/CIRCULATIONAHA.105.575993
M3 - Article
C2 - 16505177
AN - SCOPUS:33645514606
VL - 113
SP - 1226
EP - 1234
JO - Circulation
JF - Circulation
SN - 0009-7322
IS - 9
ER -