| First Author | Huo R | Year | 2019 |
| Journal | Heart Rhythm | Volume | 16 |
| Issue | 11 | Pages | 1720-1728 |
| PubMed ID | 31125668 | Mgi Jnum | J:299427 |
| Mgi Id | MGI:6490869 | Doi | 10.1016/j.hrthm.2019.05.015 |
| Citation | Huo R, et al. (2019) Enhancement of beta-catenin/T-cell factor 4 signaling causes susceptibility to cardiac arrhythmia by suppressing NaV1.5 expression in mice. Heart Rhythm 16(11):1720-1728 |
| abstractText | BACKGROUND: beta-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 beta-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 beta-catenin (beta-catDeltaE3) was used to determine the role of beta-catenin gain of function in the regulation of cardiac rhythm. RESULTS: Western blotting showed beta-catDeltaE3 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 beta1 to beta4 expression in these hearts. Immunofluorescence revealed accumulation of beta-catDeltaE3 in the nuclei of CTNNB1 E3(-/-) cardiomyocytes. Immunohistochemistry demonstrated nuclear localization of beta-catenin in cardiomyocytes, which was associated with significantly decreased NaV1.5 messenger RNA in human ischemic hearts. Immunoprecipitation revealed that beta-catDeltaE3 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 beta-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. |
