Conditional Cardiac Overexpression of S100A6 Attenuates Myocyte Hypertrophy and Apoptosis Following Myocardial Infarction

S100A6, a 20 kDa, Ca2+ - binding dimer with low basal cardiac expression, is upregulated in the rat heart following infarction and forced expression of S100A6 in rat neonatal cardiac myocyte cultures, inhibited the induction of beta myosin heavy chain (MHC), skeletal alpha actin (skACT) and myocyte apoptosis in response to diverse stimuli including tumor necrosis factor alpha. 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 myocyterestricted (alpha MHC) expression of tTA (alpha MHC-tTA). We compared S100A6-alpha MHC-tTA mice 35 days post-myocardial infarction (MI) produced by coronary artery ligation with similar matched sham-operated controls on (S100A6 transgene overexpressed) or off (S100A6 transgene silenced) DOX. There were no differences between the sham groups on or off DOX. Thirty five days post-MI, myocardial S100A6 levels increased 12.5-fold in S100A6-alpha-MHC-tTA mice off DOX compared with S100A6-alpha-MHC-tTA mice on DOX. Hemodynamic studies, echocardiography and postmortem examination indicated that S100A6-alpha MHC-tTA mice on DOX 35 days post-MI mounted a hypertrophic response (20-22.5 % increase) accompanied by a program of fetal gene re-expression, fibrosis and myocardial apoptosis. Whereas the S100A6-alpha-MHC-tTA mice off DOX showed an attenuated myocyte hypertrophic response, less fibrosis and apoptosis which was beneficial to preservation of cardiac function. Therefore, S100A6 is a potential therapeutic target for modulation of adverse left ventricular remodeling in the early post infarct period.