RAGE and modulation of ischemic injury in the diabetic myocardium.
OBJECTIVE
Subjects with diabetes experience an increased risk of myocardial infarction and cardiac failure compared with nondiabetic age-matched individuals. The receptor for advanced glycation end products (RAGE) is upregulated in diabetic tissues. In this study, we tested the hypothesis that RAGE affected ischemia/reperfusion (I/R) injury in the diabetic myocardium. In diabetic rat hearts, expression of RAGE and its ligands was enhanced and localized particularly to both endothelial cells and mononuclear phagocytes.


METHODS
To specifically dissect the impact of RAGE, homozygous RAGE-null mice and transgenic (Tg) mice expressing cytoplasmic domain-deleted RAGE (DN RAGE), in which RAGE-dependent signal transduction was deficient in endothelial cells or mononuclear phagocytes, were rendered diabetic with streptozotocin. Isolated perfused hearts were subjected to I/R.


RESULTS
Diabetic RAGE-null mice were significantly protected from the adverse impact of I/R injury in the heart, as indicated by decreased release of LDH and lower glycoxidation products carboxymethyl-lysine (CML) and pentosidine, improved functional recovery, and increased ATP. In diabetic Tg mice expressing DN RAGE in endothelial cells or mononuclear phagocytes, markers of ischemic injury and CML were significantly reduced, and levels of ATP were increased in heart tissue compared with littermate diabetic controls. Furthermore, key markers of apoptosis, caspase-3 activity and cytochrome c release, were reduced in the hearts of diabetic RAGE-modified mice compared with wild-type diabetic littermates in I/R.


CONCLUSIONS
These findings demonstrate novel and key roles for RAGE in I/R injury in the diabetic heart.
Bucciarelli
Loredana G
LG
Division of Surgical Science, Department of Surgery, Columbia University Medical Center, New York, New York, USA.
Ananthakrishnan
Radha
R
Hwang
Yuying C
YC
Kaneko
Michiyo
M
Song
Fei
F
Sell
David R
DR
Strauch
Christopher
C
Monnier
Vincent M
VM
Yan
Shi Fang
SF
Schmidt
Ann Marie
AM
Ramasamy
Ravichandran
R
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D003925:Diabetic Angiopathies / Q000235:genetics*; D007328:Insulin / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017202:Myocardial Ischemia / Q000235:genetics*; D051381:Rats; D011913:Rats, Inbred BB; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D018487:Ventricular Dysfunction, Left / Q000235:genetics
D007328:Insulin; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic