Abstract 214: S100A6 Promotes Myocyte Survival by Interacting with the Receptor for Advanced Glycation End Products and Activating Akt
The receptor for advanced ligation end-products (RAGE) recognizes ligands from diverse families including the S100 calcium binding proteins S100A6 and S100B. In a rat model of myocardial infarction, we have reported the induction of S100B, the upregulation of S100A6 and RAGE mRNA and protein in peri-infarct left ventricular (LV) myocardium, increases in S100B and S1006 serum levels and 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 deletion mutant of RAGE with S100B and/or S100A6 for 48 hrs. In RAGE overexpressing myocytes, although both S100 proteins induced the formation of reactive oxygen species, S100B > 10 nM induced myocyte apoptosis, as evidenced by increased terminal deoxynucleotidyltransferase-mediated UTP end labeling (TUNEL), FITC annexin V flow cytometry, cytochrome C release, phosphorylation of ERK1/2 and p53, and increased activity of caspase-3, whereas S100A6 < 10 nM inhibited basal myocyte apoptosis, increased the phosphorylation of Akt and the expression of NF-κB 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)]. The upstream Akt blocker LY294002, inhibited the RAGE dependent anti-apoptotic effects of S100A6 on basal- and S100B-induced myocyte apoptosis. In myocytes expressing dominant-negative RAGE, the contrasting effects of S100B and S100A6 on myocyte apoptosis were absent regardless of Akt inhibition. In conclusion, in a RAGE-dependent manner, S100A6 inhibits myocyte apoptosis via Akt activation.