S100B Interaction With the Receptor for Advanced Glycation End Products (RAGE): A Novel Receptor-Mediated Mechanism for Myocyte Apoptosis Postinfarction
Abstract
Rationale : Post–myocardial infarction ventricular remodeling is associated with the expression of a variety of factors including S100B that can potentially modulate myocyte apoptosis. Objective : This study was undertaken to investigate the expression and function of S100B and its receptor, the receptor for advanced glycation end products (RAGE) in both postinfarction myocardium and in a rat neonatal myocyte culture model. Methods and Results : In a rat model of myocardial infarction following coronary artery ligation, we demonstrate in periinfarct myocytes, upregulation of RAGE, induction of S100B, and release into plasma with consequent myocyte apoptosis. Using a coimmunoprecipitation strategy, we demonstrate a direct interaction between S100B and RAGE. In rat neonatal cardiac myocyte cultures, S100B at concentrations ≥50 nmol/L induced myocyte apoptosis, as evidenced by increased terminal DNA fragmentation, TUNEL, cytochrome c release from mitochondria to cytoplasm, phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and p53, increased expression and activity of proapoptotic caspase-3, and decreased expression of antiapoptotic Bcl-2. Transfection of a full-length cDNA of RAGE or a dominant-negative mutant of RAGE resulted in increased or attenuated S100B-induced myocyte apoptosis, respectively. Inhibition of ERK1/2 by U0126/PD-98059 or overexpression of a dominant negative p53 comparably inhibited S100B-induced myocyte apoptosis. Conclusions : These results suggest that interaction of RAGE and its ligand S100B after myocardial infarction may play a role in myocyte apoptosis by activating ERK1/2 and p53 signaling. This receptor-mediated mechanism is uniquely amenable to therapeutic intervention.
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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 [61]
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- Authors
- Tsoporis, J. N., Izhar, S., Leong-Poi, H., Desjardins, J.-F., Huttunen, H. J., & Parker, T. G.
- Affiliations
- St. Michael's Hospital (CA)
- Venue
- Circulation Research
- Published
- 2010-01-08
- Volume
- 106
- Issue
- 1
- Pages
- 93-101
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2148254624
- Cited by
- 118
- References
- 55
- Citations by year
- 2026: 2 · 2025: 10 · 2024: 2 · 2023: 7 · 2022: 4 · 2021: 12 · 2020: 4 · 2019: 6 · 2018: 6 · 2017: 5 · 2016: 5 · 2015: 5 · 2014: 7 · 2013: 8 · 2012: 21
- FWCI
- 7.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › S100 Proteins and Annexins
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Keywords
- S100B, receptor for advanced glycation end products, RAGE, myocardial infarction, cardiomyocyte apoptosis, ERK signaling, p53, caspase-3, Bcl-2, cytochrome c release
- MeSH terms
- Receptor for Advanced Glycation End Products, Animals, Butadienes, Cell Line, Cytosol, Disease Models, Animal, Enzyme Inhibitors, Flavonoids, Gene Expression Regulation, Humans, Mitochondria, Heart, Muscle Proteins, Myocardial Infarction, Nerve Growth Factors, S100 Proteins, Nitriles, Phosphorylation, Receptors, Immunologic, Signal Transduction, Tumor Suppressor Protein p53, Rats, Sprague-Dawley, Apoptosis, Ventricular Remodeling, Myocytes, Cardiac, Cytochromes c, Mitogen-Activated Protein Kinase 3, Rats, Caspase 3, DNA Fragmentation, S100 Calcium Binding Protein beta Subunit
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