RAGE and Modulation of Ischemic Injury in the Diabetic Myocardium
- Loredana G. Bucciarelli,
- Radha Ananthakrishnan,
- Yuying C. Hwang,
- Michiyo Kaneko,
- Fei Song,
- David R. Sell,
- Christopher Strauch,
- Vincent M. Monnier,
- Shi Fang Yan,
- Ann Marie Schmidt and
- Ravichandran Ramasamy
- From the Division of Surgical Science, Department of Surgery, Columbia University Medical Center, New York, New York; and the Department of Pathology, Case Western Reserve University, Cleveland, Ohio
- Corresponding author: Dr. Ravichandran Ramasamy, rr260{at}columbia.edu
Abstract
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.
RESEARCH DESIGN AND 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.
Footnotes
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Published ahead of print at http://diabetes.diabetesjournals.org on 16 April 2008.
L.G.B. is currently affiliated with Istituto Clinico Humanitas, Istituto di Ricovero e Cura a Carattere Scientifico, Rozzano, Italy.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Accepted April 9, 2008.
- Received March 19, 2007.
- DIABETES
