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-MerCreMerhet/Foxp1flox/flox/Foxp4flox/flox) and, to account for potential nonspecific Cre-mediated cardiotoxicity, we compared them to alphaMHC-MerCreMerhet 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 <0.0001) and fractional shortening (KO 12% vs. control 28%; p < 0.0001); increased left ventricular mass index (4.03 vs. 3.02 mg/kg; p = 0.004) and no change in ventricular wall thickness (p=ns). Contrary to many heart failure models, quantitative RT-PCR suggested a decrease both alpha- and beta-myosin heavy chains in KO compared to control. KO mice died from heart failure within 14 days after completing tamoxifen, whereas all controls survived. These findings indicate that Foxp transcription factors are required to maintain cardiac structure and function in the adult heart. We speculate that Foxp's repress developmental transcriptional programs that, when de-repressed in adulthood, induce cardiac myocyte dysfunction and failure.
- © 2011 by American Heart Association, Inc.