Receptor for advanced-glycation end products: key modulator of myocardial ischemic injury.
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.


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.
Bucciarelli
Loredana G
LG
Division of Surgical Science, Department of Surgery, Columbia University Medical Center, New York, NY 10032, USA.
Kaneko
Michiyo
M
Ananthakrishnan
Radha
R
Harja
Evis
E
Lee
Larisse K
LK
Hwang
Yuying C
YC
Lerner
Shulamit
S
Bakr
Soliman
S
Li
Qing
Q
Lu
Yan
Y
Song
Fei
F
Qu
Wu
W
Gomez
Teodoro
T
Zou
Yu Shan
YS
Yan
Shi Fang
SF
Schmidt
Ann Marie
AM
Ramasamy
Ravichandran
R
D000818:Animals; D006152:Cyclic GMP / Q000032:analysis; D004734:Energy Metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017202:Myocardial Ischemia / Q000378:metabolism / Q000473:pathology*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology*; D009569:Nitric Oxide / Q000032:analysis; D052247:Nitric Oxide Synthase Type II / Q000032:analysis; D051381:Rats; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000172:deficiency / Q000502:physiology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis; D015854:Up-Regulation
D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D052247:Nitric Oxide Synthase Type II; D006152:Cyclic GMP