Abstract 16203: Deletion of Foxp Repressors Induces Rapid-Onset Cardiomyopathy in Adult Mice

Transcriptomic studies in the human and murine heart have demonstrated that forkhead (FOX) binding motifs are enriched within the promoters of regulated heart failure genes, but a functional link between FOX repressors and adult heart failure has not been established. Here we demonstrate that disruption of Foxp signaling in the adult heart is sufficient to cause heart failure. Quantitative RT-PCR studies in isolated myocytes demonstrate that Foxp1 and Foxp4 are among the most highly expressed FOX transcription factors (TFs) in myocytes. As these TFs are known to repress transcription via formation of homo- and hetero-dimers, we used the MerCreMer system to delete both factors in the adult mouse heart. We created tamoxifen- inducible cardiac-specific knockout (KO) mice (alphaMHC-MerCreMer het /Foxp1 flox/flox /Foxp4 flox/flox ) and, to account for potential nonspecific Cre-mediated cardiotoxicity, we compared them to alphaMHC-MerCreMer het controls. After treatment with intraperitoneal tamoxifen at ∼3 months of age, controls remained normal, but KO animals developed signs of heart failure and a profound cardiomyopathy characterized by a drop in ejection fraction (KO 27 % vs. control 55%; p