S100B Interaction With the Receptor for Advanced Glycation End Products (RAGE): A Novel Receptor-Mediated Mechanism for Myocyte Apoptosis Postinfarction

• Published in: Circulation research 2010-01, Vol.106 (1), p.93-101
• Main Authors: Tsoporis, J N, Izhar, S, Leong-Poi, H, Desjardins, J -F, Huttunen, H J, Parker, T G
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Biological and medical sciences; Butadienes - pharmacology; Cardiology. Vascular system; Caspase 3 - genetics; Caspase 3 - metabolism; Cell Line; Coronary heart disease; Cytochromes c - genetics; Cytochromes c - metabolism; Cytosol - metabolism; Disease Models, Animal; DNA Fragmentation - drug effects; Enzyme Inhibitors - pharmacology; Flavonoids - pharmacology; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Heart; Humans; Medical sciences; Mitochondria, Heart - genetics; Mitochondria, Heart - metabolism; Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 3 - genetics; Mitogen-Activated Protein Kinase 3 - metabolism; Muscle Proteins - antagonists & inhibitors; Muscle Proteins - genetics; Muscle Proteins - metabolism; Myocardial Infarction - genetics; Myocardial Infarction - metabolism; Myocarditis. Cardiomyopathies; Myocytes, Cardiac - metabolism; Nerve Growth Factors - genetics; Nerve Growth Factors - metabolism; Nitriles - pharmacology; Phosphorylation - drug effects; Phosphorylation - genetics; Rats; Rats, Sprague-Dawley; Receptor for Advanced Glycation End Products; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; S100 Calcium Binding Protein beta Subunit; S100 Proteins - genetics; S100 Proteins - metabolism; Signal Transduction - drug effects; Signal Transduction - genetics; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Ventricular Remodeling - drug effects; Ventricular Remodeling - genetics; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.109.195834

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.