Epigenetic regulation of cardiac electrophysiology in atrial fibrillation: HDAC2 determines action potential duration and suppresses NRSF in cardiomyocytes
Atrial fibrillation (AF) is associated with electrical remodeling, leading to cellular electrophysiological dysfunction and arrhythmia perpetuation. Emerging evidence suggests a key role for epigenetic mechanisms in the regulation of ion channel expression. Histone deacetylases (HDACs) control gene...
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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
25 February 2021
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| In: |
Basic research in cardiology
Year: 2021, Jahrgang: 116, Pages: 1-11 |
| ISSN: | 1435-1803 |
| DOI: | 10.1007/s00395-021-00855-x |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1007/s00395-021-00855-x
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| Verfasserangaben: | Patrick Lugenbiel, Katharina Govorov, Pascal Syren, Ann-Kathrin Rahm, Teresa Wieder, Maximilian Wunsch, Nadine Weiberg, Emili Manolova, Dominik Gramlich, Rasmus Rivinius, Daniel Finke, Lorenz H. Lehmann, Patrick A. Schweizer, Derk Frank, Fadwa A. El Tahry, Claus Bruehl, Tanja Heimberger, Steffi Sandke, Tanja Weis, Patrick Most, Bastian Schmack, Arjang Ruhparwar, Matthias Karck, Norbert Frey, Hugo A. Katus, Dierk Thomas |
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| 245 | 1 | 0 | |a Epigenetic regulation of cardiac electrophysiology in atrial fibrillation |b HDAC2 determines action potential duration and suppresses NRSF in cardiomyocytes |c Patrick Lugenbiel, Katharina Govorov, Pascal Syren, Ann-Kathrin Rahm, Teresa Wieder, Maximilian Wunsch, Nadine Weiberg, Emili Manolova, Dominik Gramlich, Rasmus Rivinius, Daniel Finke, Lorenz H. Lehmann, Patrick A. Schweizer, Derk Frank, Fadwa A. El Tahry, Claus Bruehl, Tanja Heimberger, Steffi Sandke, Tanja Weis, Patrick Most, Bastian Schmack, Arjang Ruhparwar, Matthias Karck, Norbert Frey, Hugo A. Katus, Dierk Thomas |
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| 520 | |a Atrial fibrillation (AF) is associated with electrical remodeling, leading to cellular electrophysiological dysfunction and arrhythmia perpetuation. Emerging evidence suggests a key role for epigenetic mechanisms in the regulation of ion channel expression. Histone deacetylases (HDACs) control gene expression through deacetylation of histone proteins. We hypothesized that class I HDACs in complex with neuron-restrictive silencer factor (NRSF) determine atrial K+ channel expression. AF was characterized by reduced atrial HDAC2 mRNA levels and upregulation of NRSF in humans and in a pig model, with regional differences between right and left atrium. In vitro studies revealed inverse regulation of Hdac2 and Nrsf in HL-1 atrial myocytes. A direct association of HDAC2 with active regulatory elements of cardiac K+ channels was revealed by chromatin immunoprecipitation. Specific knock-down of Hdac2 and Nrsf induced alterations of K+ channel expression. Hdac2 knock-down resulted in prolongation of action potential duration (APD) in neonatal rat cardiomyocytes, whereas inactivation of Nrsf induced APD shortening. Potential AF-related triggers were recapitulated by experimental tachypacing and mechanical stretch, respectively, and exerted differential effects on the expression of class I HDACs and K+ channels in cardiomyocytes. In conclusion, HDAC2 and NRSF contribute to AF-associated remodeling of APD and K+ channel expression in cardiomyocytes via direct interaction with regulatory chromatin regions. Specific modulation of these factors may provide a starting point for the development of more individualized treatment options for atrial fibrillation. | ||
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