Abstract 20219: Foxc2 Plays a Key Role in the Early Response to Cardiac Ischemia via Regulation of Cardiomyocyte Apoptosis

Introduction: We have previously shown that forkhead box transcription factor C2 (Foxc2) plays a crucial role in angiogenesis. While Foxc2 has been implicated in cardiovascular disease, its role in the adult heart under pathological conditions and its underlying mechanism remain poorly understood. Hypothesis: We hypothesized that, in response to ischemic injury, Foxc2 acts through a cell-type-specific regulation of apoptosis. Methods: To test this hypothesis, mice heterozygous for either the Foxc2 global knockout (Foxc2+/-) or endothelial specific knockout (EC-Foxc2+/-), along with litter-mate controls, were subjected to myocardial infarction (MI) followed by echocardiographic analysis or whole-heart perfusion and harvest at baseline, or days 1, 3, 7, 14, or 28 post-MI. Hearts were then processed for histological staining, digested for flow cytometry, or further dissected for expression analysis. Results/ Conclusion: Time-course analysis of wild-type mice following MI revealed elevated border-zone Foxc2 mRNA 1 day post-MI, peaking at 3 days, and remaining highly elevated through day 7. Global Foxc2+/- mice subjected to ischemic injury displayed increased fibrotic scar tissue and impairment of cardiac function growing more significant with time, while EC-Foxc2+/- mice showed no change as measured by echocardiography and Masson’s Trichrome stain. Dual staining of TUNEL and lectin revealed increased border-zone apoptosis in global Foxc2+/- mice but no change in neovascularization. Analytical flow cytometry showed no difference in endothelial-specific apoptosis or cardiac leukocyte recruitment in global Foxc2+/- mice. Investigation of day 3 border-zone mRNA levels showed up-regulation of several pro-apoptotic genes including p53 and caspase3 in global Foxc2+/- hearts. Additionally, TUNEL and desmin co-staining confirmed a significant increase in cardiomyocyte-specific apoptosis 3 days post-MI. Our findings document that, in the early response to ischemic insult, Foxc2 acts through regulation of cardiomyocyte survival but not regulation of endothelial cell survival or leukocyte recruitment. Further investigation is warranted to elucidate the exact link between the protective effects of Foxc2 and cardiomyocyte survival.