Abstract 17018: β-Catenin Interacts with both FoxO1 and TCF-4 to Suppress NaV1.5 Expression after Myocardial Infarction
Introduction: Ventricular tachycardia and fibrillation (VT/VF) are the leading causes of morbidity and mortality after myocardial infarction (MI). Dysfunction of ion channels is the main mechanism underlying VT/VF. Reactive oxidative species (ROS) promote the interaction between β-catenin and FoxO1 that affects the targeting gene expression. Our previous study revealed that both TCF-4 and FoxO1 are required for β-catenin to suppress NaV1.5 expression in cardiomyocytes, but it is unknown if this process contributes to the development of VT/VF after MI.
Hypothesis: We hypothesized that β-catenin interacts with FoxO1 and TCF-4 to suppress cardiac NaV1.5 expression after MI.
Methods: Immunohistochemistry was used to determine the cellular localization of β-catenin, FoxO1 and TCF-4 in 3 human hearts with ischemic heart disease (IHD) and 3 relatively normal controls. Mouse MI was induced by ligation of the left anterior descending coronary artery (LAD). NaV1.5 expression in the peri-infarct zone (PIZ) of mouse hearts one week after MI and in H2O2-treated HL-1 cells were detected by qRT-PCR and Western blot, respectively. Distribution of β-catenin and expression of NaV1.5 protein in HL-1 cells were determined using confocal microscopy. Immunoprecipitation (IP) was performed to define the interaction of β-catenin with FoxO1 and TCF-4 in HL-1 cells.
Results: The expression of NaV1.5 was reduced at both mRNA and protein levels in PIZ, compared to the sham group. NaV1.5 protein was significantly decreased in HL-1 cells after 100 μM and 200 μM H2O2 treatment mimicking oxidative stress. β-catenin and FoxO1 were more localized in the nuclei of cardiomyocytes in human IHD, compared to controls, but TCF-4 was not altered. Although 200 μM H2O2 treatment did not affect β-catenin protein levels in HL-1 cells, it promoted β-catenin translocation from the cytoplasm into the nucleus. IP revealed that β-catenin interacted with FoxO1 and TCF-4 protein in HL-1 cells.
Conclusions: β-catenin interacts with FoxO1 and TCF-4 to suppress NaV1.5 expression after MI. These findings provide a new insight into the molecular mechanisms underlying the ROS-induced the decrease of NaV1.5 related to the development of VT/VF in MI.
Author Disclosures: N. Wang: None. B. Cai: None. Y. Lu: None. B. Ye: None. X. Li: None. F. Li: None. H. Xu: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.