Receptor for Advanced-Glycation End Products: Key Modulator of Myocardial Ischemic Injury
Abstract
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.
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In cardiomyocytes, AGEs regulate the response to ischemia-reperfusion injury via modulation of cardiac energy metabolism.
“Furthermore, it has been suggested that in cardiomyocytes AGEs regulate the response to ischemia-reperfusion injury via modulation of cardiac energy metabolism (33).”
From Cardiac remodeling in obesity (2008) · cites this paper as [33]
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- Authors
- Bucciarelli, L. G., Kaneko, M., Ananthakrishnan, R., Harja, E., Lee, L. K., Hwang, Y. C., Lerner, S., Bakr, S., Li, Q., Lu, Y., Song, F., Qu, W., Gomez, T., Zou, Y. S., Yan, S. F., Schmidt, A. M., & Ramasamy, R.
- Affiliations
- Columbia University Irving Medical Center (US)
- ORCID
- Venue
- Circulation
- Published
- 2006-03-07
- Volume
- 113
- Issue
- 9
- Pages
- 1226-1234
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2148329662
- Cited by
- 256
- References
- 40
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 4 · 2023: 3 · 2022: 7 · 2021: 15 · 2020: 13 · 2019: 9 · 2018: 7 · 2017: 11 · 2016: 13 · 2015: 16 · 2014: 9 · 2013: 27 · 2012: 17
- FWCI
- 13.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Juvenile Diabetes Research Foundation International
- American Heart Association
- Fondation Leducq
- National Heart, Lung, and Blood Institute (P01HL060901, HL 61783, HL60901, R01HL068954, HL68954, R01HL061783)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
- Keywords
- receptor for advanced glycation end products, RAGE, myocardial ischemia-reperfusion injury, cardiomyocyte death, soluble RAGE, inducible nitric oxide synthase, nitric oxide, cyclic GMP, nitrotyrosine, myocardial energy metabolism, cardiac function recovery
- MeSH terms
- Receptor for Advanced Glycation End Products, Animals, Energy Metabolism, Cyclic GMP, Male, Nitric Oxide, Receptors, Immunologic, Tyrosine, Myocardial Reperfusion Injury, Up-Regulation, Myocardial Ischemia, Mice, Knockout, Mice, Rats, Nitric Oxide Synthase Type II
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