Inhibition of histone deacetylases induces K+ channel remodeling and action potential prolongation in HL-1 atrial cardiomyocytes
<b><i>Background/Aims:</i></b> Cardiac arrhythmias are triggered by environmental stimuli that may modulate expression of cardiac ion channels. Underlying epigenetic regulation of cardiac electrophysiology remains incompletely understood. Histone deacetylases (HDACs) control...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
22 August, 2018
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| In: |
Cellular physiology and biochemistry
Year: 2018, Volume: 49, Issue: 1, Pages: 65-77 |
| ISSN: | 1421-9778 |
| DOI: | 10.1159/000492840 |
| Online Access: | Verlag, Volltext: https://doi.org/10.1159/000492840 Verlag, Volltext: https://www.karger.com/Article/FullText/492840 
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| Author Notes: | Patrick Lugenbiel, Katharina Govorov, Ann-Kathrin Rahm, Teresa Wieder, Dominik Gramlich, Pascal Syren, Nadine Weiberg, Claudia Seyler, Hugo A. Katus, Dierk Thomas |
| Summary: | <b><i>Background/Aims:</i></b> Cardiac arrhythmias are triggered by environmental stimuli that may modulate expression of cardiac ion channels. Underlying epigenetic regulation of cardiac electrophysiology remains incompletely understood. Histone deacetylases (HDACs) control gene expression and cardiac integrity. We hypothesized that class I/II HDACs transcriptionally regulate ion channel expression and determine action potential duration (APD) in cardiac myocytes. <b><i>Methods:</i></b> Global class I/II HDAC inhibition was achieved by administration of trichostatin A (TSA). HDAC-mediated effects on K<sup>+</sup> channel expression and electrophysiological function were evaluated in murine atrial cardiomyocytes (HL-1 cells) using real-time PCR, Western blot, and patch clamp analyses. Electrical tachypacing was employed to recapitulate arrhythmia-related effects on ion channel remodeling in the absence and presence of HDAC inhibition. <b><i>Results:</i></b> Global HDAC inhibition increased histone acetylation and prolonged APD<sub>90</sub> in atrial cardiomyocytes compared to untreated control cells. Transcript levels of voltage-gated or inwardly rectifying K<sup>+</sup> channels <i>Kcnq1, Kcnj3</i> and <i>Kcnj5</i> were significantly reduced, whereas <i>Kcnk2, Kcnj2</i> and <i>Kcnd3</i> mRNAs were upregulated. Ion channel remodeling was similarly observed at protein level. Short-term tachypacing did not induce significant transcriptional K<sup>+</sup> channel remodeling. <b><i>Conclusion:</i></b> The present findings link class I/II HDAC activity to regulation of ion channel expression and action potential duration in atrial cardiomyocytes. Clinical implications for HDAC-based antiarrhythmic therapy and cardiac safety of HDAC inhibitors require further investigation. |
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| Item Description: | Das Pluszeichen im Titel ist hochgestellt Gesehen am 24.07.2019 |
| Physical Description: | Online Resource |
| ISSN: | 1421-9778 |
| DOI: | 10.1159/000492840 |