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Epigenetic regulation of cardiac electrophysiology in atrial fibrillation: HDAC2 determines action potential duration and suppresses NRSF in cardiomyocytes

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Abstract

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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Availability of data and material

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgments

We thank Teresa Caspari, Xenia Kramp, and Axel Schöffel for excellent technical assistance, and the operating room team at the Department of Cardiac Surgery of Heidelberg University for supporting our work.

Funding

This work was supported in part by research grants from the University of Heidelberg, Faculty of Medicine (Postdoctoral Fellowships to P.L. and to A.K.R.), from the German Cardiac Society (Fellowships to P.L. and to A.K.R., Otto-Hess-Promotionsstipendium to D.G.), from the Ernst und Berta Grimmke-Stiftung (to P.L.), from the Elisabeth und Rudolf-Hirsch Stiftung für Medizinische Forschung (to A.K.R), from the German Heart Foundation/German Foundation of Heart Research (F/08/14 to D.T., Fellowship to A.K.R, Kaltenbach-Promotionsstipendium to K.G., D.G. and M.W.), from the German Internal Medicine Society (Clinician-Scientist-Program to A.K.R.), from the Joachim Siebeneicher Foundation (to D.T.), from the Deutsche Forschungsgemeinschaft (German Research Foundation; SCHW 1611/-1 to P.A.S; TH 1120/7-1 and TH 1120/8-1 to D.T.), and from the Ministry of Science, Research and the Arts Baden-Wuerttemberg (Sonderlinie Medizin to D.T.). P.A.S is recipient of the Heidelberg Research Center for Molecular Medicine (HRCMM) Senior Career Fellowship. T.W. and D.G. were supported by the Cardiology Career Program of the Department of Cardiology, University of Heidelberg.

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Authors and Affiliations

  1. Department of Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany

    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, Fadwa A. El Tahry, Tanja Heimberger, Steffi Sandke, Tanja Weis, Patrick Most, Norbert Frey, Hugo A. Katus & Dierk Thomas

  2. HCR (Heidelberg Center for Heart Rhythm Disorders), Heidelberg, Germany

    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, Norbert Frey, Hugo A. Katus & Dierk Thomas

  3. DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, University of Heidelberg, Heidelberg, Germany

    Ann-Kathrin Rahm, Maximilian Wunsch, Dominik Gramlich, Rasmus Rivinius, Patrick A. Schweizer, Fadwa A. El Tahry, Tanja Heimberger, Steffi Sandke, Tanja Weis, Patrick Most, Norbert Frey, Hugo A. Katus & Dierk Thomas

  4. Department of Molecular Cardiology and Epigenetics, University Hospital Heidelberg, Heidelberg, Germany

    Daniel Finke & Lorenz H. Lehmann

  5. Department of Internal Medicine III, Cardiology and Angiology, University Medical Center Schleswig-Holstein, Kiel, Germany

    Derk Frank & Norbert Frey

  6. DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, University Medical Center Schleswig-Holstein, Kiel, Germany

    Derk Frank & Norbert Frey

  7. Institute for Physiology and Pathophysiology, Heidelberg, Germany

    Claus Bruehl

  8. Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany

    Bastian Schmack, Arjang Ruhparwar & Matthias Karck

Authors
  1. Patrick Lugenbiel
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  2. Katharina Govorov
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  3. Pascal Syren
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  4. Ann-Kathrin Rahm
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  5. Teresa Wieder
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  6. Maximilian Wunsch
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  7. Nadine Weiberg
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  8. Emili Manolova
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  9. Dominik Gramlich
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  11. Daniel Finke
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  13. Patrick A. Schweizer
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  14. Derk Frank
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  20. Patrick Most
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  26. Dierk Thomas
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Contributions

PL and DT conceived the study. PL, KG, PS, AKR, and DT designed the experiments. PL, KG, PS, AKR, TWi, MW, NW, EM, DG, RR, DFi, LHL, PAS, DFr, FAET, CB, TH, SS, TWe, PM, BS, and AR performed the experiments. All authors contributed to data analysis and interpretation. PL and DT wrote the manuscript. All authors contributed to critical review and editing of the manuscript.

Corresponding author

Correspondence to Dierk Thomas.

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Conflicts of interest

P.L. reports receiving lecture fees from Bayer Vital and Pfizer Pharma and educational support from Boston Scientific and Johnson & Johnson. A.K.R. reports educational support from Boston Scientific, Johnson & Johnson, Abbott and Medtronic. D.T. reports receiving lecture fees/honoraria from Bayer Vital, Boehringer Ingelheim Pharma, Bristol-Myers Squibb, Daiichi Sankyo, Medtronic, Pfizer Pharma, Sanofi-Aventis, St. Jude Medical and ZOLL CMS. The remaining authors have reported that they have no relationships relevant to the content of this paper to disclose.

Ethics approval

Human cardiac tissue samples were obtained from HF patients in accordance with the Declaration of Helsinki and with the regulations of the tissue bank of the National Center for Tumor Diseases (NCT, Heidelberg, Germany), following approval of the Ethics Committee of Heidelberg University (Heidelberg, Germany) (institutional approval number S-390/2011). Heart tissue samples from SR patients with preserved left ventricular function were acquired in accordance with the Declaration of Helsinki following approval of the Ethics Committee of Heidelberg University (Heidelberg, Germany) (institutional approval number S295/2018). Written informed consent was obtained from all patients. Animal experiments in this study have been carried out in accordance with the Guide for the Care and Use of Laboratory Animals as adopted and promulgated by the U.S. National Institutes of Health (NIH publication No. 85–23, revised 1985), and the current version of the German Law on the Protection of Animals was followed. The investigation conforms to the Directive 2010/63/EU of the European Parliament. Cardiac tissue acquisition from pigs 7 days (ethics approval number G-106/10) or 14 days (ethics approval number G-165/12) after the initiation of atrial burst pacing and from control pigs not subjected to burst pacing was approved be the Animal Welfare Committee of the Regierungspräsidium Karlsruhe (Karlsruhe, Germany). Experiments involving mouse cardiomyocytes were approved be the Animal Welfare Committee of the Regierungspräsidium Karlsruhe (ethics approval number T-44/18).

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Lugenbiel, P., Govorov, K., Syren, P. et al. Epigenetic regulation of cardiac electrophysiology in atrial fibrillation: HDAC2 determines action potential duration and suppresses NRSF in cardiomyocytes. Basic Res Cardiol 116, 13 (2021). https://doi.org/10.1007/s00395-021-00855-x

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