Rong Huo1, Chaowei Hu1, Limei Zhao2, Lihua Sun2, Ning Wang1, Yan Lu3, Bo Ye4, Arjun Deb5, Faqian Li4, Haodong Xu6. 1. Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California. 2. Department of Pathology, Center for Cardiovascular Biology and Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington. 3. Department of Pathology, Center for Cardiovascular Biology and Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington; Division of Cardiology, David Geffen School of Medicine, UCLA, Los Angeles, California. 4. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota. 5. Division of Cardiology, David Geffen School of Medicine, UCLA, Los Angeles, California. 6. Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California; Department of Pathology, Center for Cardiovascular Biology and Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington. Electronic address: xuh8@uw.edu.
Abstract
BACKGROUND: β-Catenin/T-cell factor 4 (TCF4) signaling is enhanced in ischemic heart disease in which ventricular tachycardia (VT)/ventricular fibrillation occurs frequently. How this signaling links to arrhythmogenesis remains unclear. OBJECTIVE: The purpose of this study was to investigate the role of β-catenin gain of function in the development of arrhythmia. METHODS: A mouse model with a conditional deletion of CTNNB1 exon 3 resulting in cardiac exon 3-deleted and stabilized β-catenin (β-catΔE3) was used to determine the role of β-catenin gain of function in the regulation of cardiac rhythm. RESULTS: Western blotting showed β-catΔE3 expression and significantly decreased NaV1.5 protein in CTNNB1 E3-/- and CTNNB1 E3+/- mouse hearts. Real-time qRT-PCR revealed significantly decreased NaV1.5 messenger RNA with no changes in Na+ channel β1 to β4 expression in these hearts. Immunofluorescence revealed accumulation of β-catΔE3 in the nuclei of CTNNB1 E3-/- cardiomyocytes. Immunohistochemistry demonstrated nuclear localization of β-catenin in cardiomyocytes, which was associated with significantly decreased NaV1.5 messenger RNA in human ischemic hearts. Immunoprecipitation revealed that β-catΔE3 interacted with TCF4 in CTNNB1 E3-/- cardiomyocytes. Whole-cell recordings showed that Na+ currents and depolarization and amplitude of action potentials were significantly decreased in CTNNB1 E3-/- ventricular myocytes. Electrocardiographic recordings demonstrated that in mice with cardiac CTNNB1 E3-/-, the QRS complex was prolonged and VT was induced by the Na+ channel blocker flecainide. However, cardiac function, as determined by echocardiography and heart/body weight ratios, remained unchanged. CONCLUSION: Enhancement of β-catenin/TCF4 signaling led to the prolongation of the QRS complex and increase in susceptibility to VT by suppression of NaV1.5 expression and Na+ channel activity in mice.
BACKGROUND: β-Catenin/T-cell factor 4 (TCF4) signaling is enhanced in ischemic heart disease in which ventricular tachycardia (VT)/ventricular fibrillation occurs frequently. How this signaling links to arrhythmogenesis remains unclear. OBJECTIVE: The purpose of this study was to investigate the role of β-catenin gain of function in the development of arrhythmia. METHODS: A mouse model with a conditional deletion of CTNNB1 exon 3 resulting in cardiac exon 3-deleted and stabilized β-catenin (β-catΔE3) was used to determine the role of β-catenin gain of function in the regulation of cardiac rhythm. RESULTS: Western blotting showed β-catΔE3 expression and significantly decreased NaV1.5 protein in CTNNB1 E3-/- and CTNNB1 E3+/- mouse hearts. Real-time qRT-PCR revealed significantly decreased NaV1.5 messenger RNA with no changes in Na+ channel β1 to β4 expression in these hearts. Immunofluorescence revealed accumulation of β-catΔE3 in the nuclei of CTNNB1 E3-/- cardiomyocytes. Immunohistochemistry demonstrated nuclear localization of β-catenin in cardiomyocytes, which was associated with significantly decreased NaV1.5 messenger RNA in humanischemic hearts. Immunoprecipitation revealed that β-catΔE3 interacted with TCF4 in CTNNB1 E3-/- cardiomyocytes. Whole-cell recordings showed that Na+ currents and depolarization and amplitude of action potentials were significantly decreased in CTNNB1 E3-/- ventricular myocytes. Electrocardiographic recordings demonstrated that in mice with cardiac CTNNB1 E3-/-, the QRS complex was prolonged and VT was induced by the Na+ channel blocker flecainide. However, cardiac function, as determined by echocardiography and heart/body weight ratios, remained unchanged. CONCLUSION: Enhancement of β-catenin/TCF4 signaling led to the prolongation of the QRS complex and increase in susceptibility to VT by suppression of NaV1.5 expression and Na+ channel activity in mice.
Authors: G Alex Papadatos; Polly M R Wallerstein; Catherine E G Head; Rosemary Ratcliff; Peter A Brady; Klaus Benndorf; Richard C Saumarez; Ann E O Trezise; Christopher L-H Huang; Jamie I Vandenberg; William H Colledge; Andrew A Grace Journal: Proc Natl Acad Sci U S A Date: 2002-04-23 Impact factor: 11.205
Authors: Srividhya Iyer; Elena Ambrogini; Shoshana M Bartell; Li Han; Paula K Roberson; Rafael de Cabo; Robert L Jilka; Robert S Weinstein; Charles A O'Brien; Stavros C Manolagas; Maria Almeida Journal: J Clin Invest Date: 2013-07-15 Impact factor: 14.808