Abstract 3608: Conditional Cardiac Overexpression of S100B Attenuates Hypertrophy and Potentiates Apoptosis Following Myocardial Infarction in Mice
Genetically engineered mouse models may be useful to evaluate the contributions of post-infarct myocardial hypertrophy to preservation of cardiac function. S100B, a 20 kDa, Ca2+-binding dimer is a putative intrinsic negative regulator of myocardial hypertrophy expressed after myocardial infarction. Here we generated cardiac myocyte-specific transgenic mice by placing the human S100B 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 S100B-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 S100B levels were increased 10-fold in S100B-αMHC-tTA mice off DOX compared with S100B-αMHC-tTA mice on DOX. The post infarct end-diastolic pressure was higher in S100B-αMHC-tTA mice off DOX than in S100B-αMHC-tTA mice on DOX. Echocardiography and postmortem examination indicated that the S100B-αMHC-tTA mice on DOX 35 days post-MI mounted a hypertrophic response (25% 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 S100B, the S100B-αMHC-tTA mice off DOX showed no detectable hypertrophy or the associated fetal gene expression, but marked peri-infarct myocyte apoptosis, as evidenced by DNA fragmentation, increased caspase-3 activity, and increased terminal deoxynucleotidyltransferase-mediated UTP end labeling (TUNEL), [0.25±0.01 (off DOX) vs 0.11±0.02 (on DOX) per cent TUNEL positive myocytes]. Therefore, S100B is a potential therapeutic target for modulation of the myocardial hypertrophic response that could be beneficial in the early post infarct period.