Abstract 2953: Conditional Cardiac Overexpression of S100A6 Attenuates Myocyte Apoptosis Post- Myocardial Infarction in Mice
S100A6, a 20 kDa, Ca2+-binding dimer is expressed after myocardial infarction and in vitro inhibits myocyte apoptosis in response to diverse stimuli including TNFα. To define a role for S100A6 in vivo, we generated cardiac myocyte-specific transgenic mice by placing the human S100A6 cDNA downstream of a promoter responsive to a doxycycline (DOX)-regulated transcriptional activator (tTA) and breeding this line with one harboring cardiac myocyte-restricted [alpha myosin heavy chain (αMHC)]expression of tTA (αMHC-tTA). We compared 12 week old S100A6-αMHC-tTA mice 35 days post-MI produced by coronary artery ligation with similar matched sham-operated controls on or off DOX. There were no significant differences between the sham groups on or off DOX. Myocardial S100BA6 levels were increased 12.5-fold in S100A6-αMHC-tTA mice off DOX compared with S100A6-αMHC-tTA mice on DOX. Echocardiography and postmortem examination indicated that S100A6-αMHC-tTA mice on or off DOX 35 days post-MI mounted a hypertrophic response (20–22.5 % increase) accompanied by a program of fetal gene re-expression including β-MHC, skeletal α-actin and atrial natriuretic factor, consistent with the proposed function of S100A6, the S100A6-αMHC-tTA mice off DOX showed less peri-infarct myocyte apoptosis, as evidenced by decreased DNA fragmentation, decreased caspase-3 activity, and decreased terminal deoxynucleotidyltransferase-mediated UTP end labeling (TUNEL), [0.15+0.01 (off DOX) vs 0.28+0.02 (on DOX) per cent TUNEL positive myocytes]. Therefore, S100A6 is a potential therapeutic target for modulation of the myocardial apoptotic response that could be beneficial in the early post infarct period.