366 Abrogation of S100B Expression in S100A1 Deficient Mice Improves Survival Post Myocardial Infarction

Abstract

Post-myocardial infarction (MI) ventricular remodeling involves ventricular dilation, hypertrophy of non-infarcted myocardium, myocyte apoptosis, the induction of S100B and the downregulation of S100A1. Whereas S100A1 deficiency results in cardiac functional impairment and high early mortality post-MI, abrogation of S100B preserves cardiac function in the setting of augmented hypertrophy post-MI. To assess the consequences of S100B expression in S100A1 knock out (KO) mice, wild-type (WT), S100A1 KO, S100B KO and S100A1-B KO 6-8 week-old mice were subjected to 35 days after left anterior descending coronary artery ligation with similar age-matched sham-operated controls. S100A1-B KO mice demonstrated better survival as compared to S100A1 KO and WT mice (79.5% vs. 28.6% vs. 69.7 % respectively, p<0.05), comparable to S100B KO mice (82.6%). Most of the deaths in S100A1 KO mice occurred 3-6 days following MI. Acute hemodynamic monitoring post-MI demonstrated that the S100A1 KO animals died of rapidly of progressive pump failure. At day 2 post-MI, S100A1 KO mice demonstrated S100B expression, increased left ventricular dilatation by echocardiography, less collagen I and III mRNAs within the infarct area, an increase in MMP-9 expression and apoptosis (as assessed by Caspase-3 activity and TUNEL staining) in the infarct border zone of versus WT. Among survivors at day 35, post mortem examination indicated that the WT and KO groups of infarcted mice mounted a hypertrophic response that was augmented in the S100B KO and S100A1-B KO groups (WT 3.95±0.21; S100A1 KO 4.05±0.13; S100B KO 4.39±0.18; S100A1-B KO 4.71±0.21 mg/g Body Weight, p<0.05 S100A1-B KO vs. S100A1 KO). The augmented hypertrophic response in the S100B KO and S100A1-B KO groups was associated with less apoptosis (as assessed by Caspase-3 activity) compared to the WT and S100A1 KO mice (WT 52.5±5.4; S100A1-KO 58.6±6.9; S100B KO 41.6±3.7; S100A1-B KO-43.8±3.5 µmol/mL, p<0.05 S100A1-B KO vs. S100A1 KO). The post infarct left ventricular end diastolic pressure was lower in S100A1-B KO and S100B KO mice compared to WT and S100A KO mice (S100A1-B KO 6.1±0.4 vs. S100A1KO 12.1±1.9 mmHg, p<0.05). Our results suggest that the abrogation of S100B expression in S100A1-B KO mice augmented hypertrophy, decreased apoptosis, preserved extracellular matrix proteins and was beneficial to the preservation of cardiac function and survival within this time frame.