RAGE modulates myocardial injury consequent to LAD infarction via impact on JNK and STAT signaling in a murine model
Abstract
The receptor for advanced glycation end-products (RAGE) has been implicated in the pathogenesis of ischemia-reperfusion (I/R) injury in the isolated perfused heart. To test the hypothesis that RAGE-dependent mechanisms modulated responses to I/R in a murine model of transient occlusion and reperfusion of the left anterior descending coronary artery (LAD), we subjected male homozygous RAGE−/− mice and their wild-type age-matched littermates to 30 min of occlusion of the LAD followed by reperfusion. At 48 h of reperfusion, hematoxylin and eosin staining revealed significantly larger infarct size in wild-type versus RAGE−/− mice. Contractile function, as evaluated by echocardiography 48 h after reperfusion, revealed that fractional shortening was significantly higher in RAGE−/− versus wild-type mice. Plasma levels of creatine kinase were markedly decreased in RAGE−/− versus wild-type animals. Integral to the impact of RAGE deletion on diminished myocardial damage after infarction was significantly decreased apoptosis in the heart, as assessed by TUNEL staining, release of cytochrome c, and caspase-3 activity. Experiments investigating the impact of RAGE on early signaling pathways influencing myocardial ischemic injury revealed attenuation of JNK and STAT5 phosphorylation in RAGE−/− mouse hearts versus robust activation observed in wild-type mice upon ischemia and reperfusion. Solidifying the link to RAGE, these experiments revealed that infarction stimulated the rapid production of advanced glycation end-products in the heart. Thus, we tested the effect of ligand decoy soluble RAGE (sRAGE). Administration of sRAGE protected the myocardium from ischemic damage, similar to the effects observed in RAGE−/− mouse hearts. Taken together, these data implicate RAGE and its ligands in the pathogenesis of I/R injury and identify JNK and STAT signal transduction as central downstream effector pathways of the ligand-RAGE axis in the heart subjected to I/R injury.
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In acute myocardial infarction, increased expression of RAGE and its interaction with AGEs, HMGB1, and S100 induce cardiomyocyte apoptosis by activating the MAPK pathway.
“In acute myocardial infarction, increased expression of RAGE and its interaction with AGEs, HMGB1, and S100 induce cardiomyocyte apoptosis by activating the MAPK pathway60,61.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [60]
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- Authors
- Aleshin, A., Ananthakrishnan, R., Li, Q., Rosario, R., Lu, Y., Qu, W., Song, F., Bakr, S., Szabolcs, M., D'Agati, V., Liu, R., Homma, S., Schmidt, A. M., Yan, S. F., & Ramasamy, R.
- Affiliations
- Columbia University (US)
- ORCID
- Venue
- American Journal of Physiology-Heart and Circulatory Physiology
- Publisher
- American Physiological Society
- Published
- 2008-04
- Volume
- 294
- Issue
- 4
- Pages
- H1823-H1832
- ISSN
- 0363-6135 (ISSN-L)
- 1522-1539
- OpenAlex
- W2129075447
- Cited by
- 143
- References
- 30
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 4 · 2023: 3 · 2022: 4 · 2021: 8 · 2020: 6 · 2019: 8 · 2018: 5 · 2017: 13 · 2016: 7 · 2015: 16 · 2014: 3 · 2013: 7 · 2012: 13
- FWCI
- 8.24
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Heart and Circulatory Physiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- 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 › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Keywords
- receptor for advanced glycation end products, myocardial ischemia-reperfusion injury, left anterior descending artery occlusion, infarct size, JNK signaling, STAT5 signaling, apoptosis, caspase-3, cytochrome c release, advanced glycation end products, soluble RAGE, cardioprotection, RAGE knockout mice
- MeSH terms
- Receptor for Advanced Glycation End Products, Animals, Coronary Vessels, Disease Models, Animal, Enzyme Activation, Ligands, Ligation, Male, Mice, Inbred C57BL, Myocardial Contraction, Myocardial Infarction, Myocardium, Phosphorylation, Receptors, Immunologic, Time Factors, Signal Transduction, Myocardial Reperfusion Injury, Glycation End Products, Advanced, Apoptosis, Mice, Knockout, JNK Mitogen-Activated Protein Kinases, STAT5 Transcription Factor, Mice, Creatine Kinase, MB Form
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