1. 14-3-3ε/YWHAE regulates the transcriptional expression of cardiac sodium channel Na V 1.5.
- Author
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Hu Y, Zhang C, Wang S, Xiong H, Xie W, Zeng Z, Cai H, Wang QK, and Lu Z
- Abstract
Background: Cardiac voltage-gated sodium channel alpha subunit 5 (Na
V 1.5) encoded by SCN5A is associated with arrhythmia disorders. However, the molecular mechanism underlying NaV 1.5 expression remains to be fully elucidated. Previous studies have reported that the 14-3-3 family acts as an adaptor involved in regulating kinetic characteristics of cardiac ion channels., Objective: The purpose of this study was to establish 14-3-3ε/YWHAE, a member of the 14-3-3 family, as a crucial regulator of NaV 1.5 and to explore the potential role of 14-3-3ε in the heart., Methods: Western blotting, patch clamping, real-time reverse transcription-polymerase chain reaction, RNA immunoprecipitation, electrocardiogram recording, echocardiography, and histologic analysis were performed., Results: YWHAE overexpression significantly reduced the expression level of SCN5A mRNA and sodium current density, whereas YWHAE knockdown significantly increased SCN5A mRNA expression and sodium current density in HEK293/NaV 1.5 and H9c2 cells. Similar results were observed in mice injected with adeno-associated virus serotype 9-mediated YWHAE knockdown. The effect of 14-3-3ε on NaV 1.5 expression was abrogated by knockdown of TBX5, a transcription factor of NaV 1.5. An interaction between 14-3-3ε protein and TBX5 mRNA was identified, and YWHAE overexpression significantly decreased TBX5 mRNA stability without affecting SCN5A mRNA stability. In addition, mice subjected to adeno-associated virus serotype 9-mediated YWHAE knockdown exhibited shorter R-R intervals and higher prevalence of premature ventricular contractions., Conclusion: Our data unveil a novel regulatory mechanism of NaV 1.5 by 14-3-3ε and highlight the significance of 14-3-3ε in transcriptional regulation of NaV 1.5 expression and cardiac arrhythmias., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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