Abstract 17995: Inhibition of Myofibroblast Differentiation by FOXO3a - Implications for Acute Myocardial Infarction and Cardiac Remodeling

Introduction: Transdifferentiation of cardiac fibroblasts into myofibroblasts regulated by TGFβ/SMAD3 signaling is a major mechanism of scar formation and adverse remodeling following myocardial infarction. Hypothesis: We hypothesized that the transcription factor FOXO3a, a key regulator of cell differentiation, cycle and size, might inhibit this process. Methods: Acute myocardial infarction was induced in FOXO3-/- and WT mice (FVB) by permanent LAD ligation and myofibroblast transdifferentiation markers were assessed. FOXO3a-/- and WT cardiac fibroblasts were investigated in transdifferentiation assays ex vivo. FOXO3a gene transfer was performed with gain of function adenoviral vectors. IP/IF and Western blotting were used to test for a direct interaction between FOXO3a and SMAD3. Results: FOXO3a-/- mice had significantly higher survival rates compared to WT mice due to reduced rates of ventricle perforation. Myocardial expression of alpha smooth muscle actin (ASMA) and Collagen1A1 (Col1A1) was significa...