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No. 57 S100a6 and s100b differentially modulate myocyte survival in a rage-dependent manner James N. Tsoporisa,⁎, Shehla Izhar, Henri J. Huttunen, Thomas G. Parker. University of Toronto, Canada. Harvard Medical School, Boston MA, USA ⁎ Corresponding author. St. Michael's Hospital, Department of Cardiology Room 6-044, Queen Wing, 30 Bond Street Toronto, Ontario, Canada M5B 1W8. Tel.: +1 416 864 6060x6133; fax: +1 416 864 5989. E-mail address: jimtsoporis@sympatico.ca The receptor for advanced ligation end-products (RAGE) recognizes ligands from diverse families including the S100 calcium binding proteins S100A6 and S100B. The expression of S100A6 andS100B and their interactionwithRAGE inmyocardial disease are unknown. In a rat model of myocardial infarction 35 days post coronary artery ligation, we show the induction of S100B, a 2-fold increase in S100A6 and RAGE mRNA and protein in peri-infarct left ventricular (LV) myocardium, and a 10-fold increase in S100B, S1006, RAGE serum levels. Coimmunoprecipitation demonstrated a direct interaction between S100B and S100A6 with RAGE in peri-infarct LV myocardium. To determine the functional role of the interaction of S100A6 and S100B with RAGE, we stimulated rat neonatal cardiac myocyte cultures transfected with a RAGE gene or a dominant-negative cytoplasmic deletionmutant of RAGEwith S100B and/or S100A6 for 48 h. In RAGE overexpressing myocytes, S100BN10 nM induced myocyte apoptosis, as evidenced by increased terminal deoxynucleotidyltransferase-mediated UTP end labeling (TUNEL), cytochrome C release, phosphorylation of ERK1/2, p38 and p53 and increased activity of caspase-3, in contrast S100A6b10 nM inhibited basal myocyte apoptosis, increased the phosphorylation of Akt and the expression of NF-kB and in combination with S100B inhibited S100B-induced myocyte apoptosis [6.3±0.9% (vehicle), 16.1±0.1.2% (S100B), 4.1± 0.4% (S100A6), 6.4±1.5% (S100B+S100A6) (TUNEL positive nuclei)]. In myocytes expressing dominant-negative RAGE, the contrasting effects of S100B and S100A6 on myocyte apoptosis were absent. In conclusion, S100B and S100A6 differentially modulate myocyte survival in a RAGE-dependent manner.