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.
Similar content being viewed by others
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.
References
Allessie M, Ausma J, Schotten U (2002) Electrical, contractile and structural remodeling during atrial fibrillation. Cardiovasc Res 54:230–246. https://doi.org/10.1016/s0008-6363(02)00258-4
Backs J, Olson EN (2006) Control of cardiac growth by histone acetylation/deacetylation. Circ Res 98:15–24. https://doi.org/10.1161/01.RES.0000197782.21444.8f
Burstein B, Nattel S (2008) Atrial fibrosis: mechanisms and clinical relevance in atrial fibrillation. J Am Coll Cardiol 51:802–809. https://doi.org/10.1016/j.jacc.2007.09.064
Campbell K, Calvo CJ, Mironov S, Herron T, Berenfeld O, Jalife J (2012) Spatial gradients in action potential duration created by regional magnetofection of hERG are a substrate for wavebreak and turbulent propagation in cardiomyocyte monolayers. J Physiol 590:6363–6379. https://doi.org/10.1113/jphysiol.2012.238758
Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M (2009) Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325:834–840. https://doi.org/10.1126/science.1175371
Dobrev D, Ravens U (2003) Remodeling of cardiomyocyte ion channels in human atrial fibrillation. Basic Res Cardiol 98:137–148. https://doi.org/10.1007/s00395-003-0409-8
Formisano L, Guida N, Valsecchi V, Cantile M, Cuomo O, Vinciguerra A, Laudati G, Pignataro G, Sirabella R, Di Renzo G, Annunziato L (2015) Sp3/REST/HDAC1/HDAC2 complex represses and Sp1/HIF-1/p300 complex activates ncx1 gene transcription, in brain ischemia and in ischemic brain preconditioning, by epigenetic mechanism. J Neurosci 35:7332–7348. https://doi.org/10.1523/JNEUROSCI.2174-14.2015
Glozak MA, Sengupta N, Zhang X, Seto E (2005) Acetylation and deacetylation of non-histone proteins. Gene 363:15–23. https://doi.org/10.1016/j.gene.2005.09.010
Gregoretti IV, Lee YM, Goodson HV (2004) Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis. J Mol Biol 338:17–31. https://doi.org/10.1016/j.jmb.2004.02.006
Kee HJ, Bae EH, Park S, Lee KE, Suh SH, Kim SW, Jeong MH (2013) HDAC inhibition suppresses cardiac hypertrophy and fibrosis in DOCA-salt hypertensive rats via regulation of HDAC6/HDAC8 enzyme activity. Kidney Blood Press Res 37:229–239. https://doi.org/10.1159/000350148
Kong Y, Tannous P, Lu G, Berenji K, Rothermel BA, Olson EN, Hill JA (2006) Suppression of class I and II histone deacetylases blunts pressure-overload cardiac hypertrophy. Circulation 113:2579–2588. https://doi.org/10.1161/CIRCULATIONAHA.106.625467
Kook H, Lepore JJ, Gitler AD, Lu MM, Wing-Man Yung W, Mackay J, Zhou R, Ferrari V, Gruber P, Epstein JA (2003) Cardiac hypertrophy and histone deacetylase-dependent transcriptional repression mediated by the atypical homeodomain protein Hop. J Clin Invest 112:863–871. https://doi.org/10.1172/JCI19137
Kuwahara K, Saito Y, Takano M, Arai Y, Yasuno S, Nakagawa Y, Takahashi N, Adachi Y, Takemura G, Horie M, Miyamoto Y, Morisaki T, Kuratomi S, Noma A, Fujiwara H, Yoshimasa Y, Kinoshita H, Kawakami R, Kishimoto I, Nakanishi M, Usami S, Saito Y, Harada M, Nakao K (2003) NRSF regulates the fetal cardiac gene program and maintains normal cardiac structure and function. EMBO J 22:6310–6321. https://doi.org/10.1093/emboj/cdg601
Li P, Kurata Y, Endang M, Ninomiya H, Higaki K, Taufiq F, Morikawa K, Shirayoshi Y, Horie M, Hisatome I (2018) Restoration of mutant hERG stability by inhibition of HDAC6. J Mol Cell Cardiol 115:158–169. https://doi.org/10.1016/j.yjmcc.2018.01.009
Li Z, Guo Y, Ren X, Rong L, Huang M, Cao J, Zang W (2019) HDAC2, but not HDAC1, regulates Kv1.2 expression to mediate neuropathic pain in CCI rats. Neuroscience 408:339–348. https://doi.org/10.1016/j.neuroscience.2019.03.033
Liu F, Levin MD, Petrenko NB, Lu MM, Wang T, Yuan LJ, Stout AL, Epstein JA, Patel VV (2008) Histone-deacetylase inhibition reverses atrial arrhythmia inducibility and fibrosis in cardiac hypertrophy independent of angiotensin. J Mol Cell Cardiol 45:715–723. https://doi.org/10.1016/j.yjmcc.2008.08.015
Lkhagva B, Chang SL, Chen YC, Kao YH, Lin YK, Chiu CT, Chen SA, Chen YJ (2014) Histone deacetylase inhibition reduces pulmonary vein arrhythmogenesis through calcium regulation. Int J Cardiol 177:982–989. https://doi.org/10.1016/j.ijcard.2014.09.175
Lkhagva B, Kao YH, Chen YC, Chao TF, Chen SA, Chen YJ (2016) Targeting histone deacetylases: a novel therapeutic strategy for atrial fibrillation. Eur J Pharmacol 781:250–257. https://doi.org/10.1016/j.ejphar.2016.04.034
Lugenbiel P, Govorov K, Rahm AK, Wieder T, Gramlich D, Syren P, Weiberg N, Seyler C, Katus HA, Thomas D (2018) Inhibition of histone deacetylases induces K+ channel remodeling and action potential prolongation in HL-1 atrial cardiomyocytes. Cell Physiol Biochem 49:65–77. https://doi.org/10.1159/000492840
Lugenbiel P, Wenz F, Govorov K, Schweizer PA, Katus HA, Thomas D (2015) Atrial fibrillation complicated by heart failure induces distinct remodeling of calcium cycling proteins. PLoS ONE 10:e0116395. https://doi.org/10.1371/journal.pone.0116395
Lugenbiel P, Wenz F, Syren P, Geschwill P, Govorov K, Seyler C, Frank D, Schweizer PA, Franke J, Weis T, Bruehl C, Schmack B, Ruhparwar A, Karck M, Frey N, Katus HA, Thomas D (2017) TREK-1 (K2P2.1) K+ channels are suppressed in patients with atrial fibrillation and heart failure and provide therapeutic targets for rhythm control. Basic Res Cardiol 112:8. https://doi.org/10.1007/s00395-016-0597-7
Montgomery RL, Davis CA, Potthoff MJ, Haberland M, Fielitz J, Qi X, Hill JA, Richardson JA, Olson EN (2007) Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractility. Genes Dev 21:1790–1802. https://doi.org/10.1101/gad.1563807
Nattel S, Maguy A, Le Bouter S, Yeh YH (2007) Arrhythmogenic ion-channel remodeling in the heart: heart failure, myocardial infarction, and atrial fibrillation. Physiol Rev 87:425–456. https://doi.org/10.1152/physrev.00014.2006
Nural-Guvener HF, Zakharova L, Nimlos J, Popovic S, Mastroeni D, Gaballa MA (2014) HDAC class I inhibitor, mocetinostat, reverses cardiac fibrosis in heart failure and diminishes CD90+ cardiac myofibroblast activation. Fibrogenesis Tissue Repair 7:10. https://doi.org/10.1186/1755-1536-7-10
Ohya S, Kanatsuka S, Hatano N, Kito H, Matsui A, Fujimoto M, Matsuba S, Niwa S, Zhan P, Suzuki T, Muraki K (2016) Downregulation of the Ca2+-activated K+ channel KCa3.1 by histone deacetylase inhibition in human breast cancer cells. Pharmacol Res Perspect 4:e00228. https://doi.org/10.1002/prp2.228
Rahm AK, Wieder T, Gramlich D, Müller ME, Wunsch MN, El Tahry FA, Heimberger T, Weis T, Most P, Katus HA, Thomas D, Lugenbiel P (2021) HDAC2-dependent remodeling of KCa2.2 (KCNN2) and KCa23 (KCNN3) K+ channels in atrial fibrillation with concomitant heart failure. Life Sci 266:118892. https://doi.org/10.1016/j.lfs.2020.11889
Schmidt C, Wiedmann F, Zhou XB, Heijman J, Voigt N, Ratte A, Lang S, Kallenberger SM, Campana C, Weymann A, De Simone R, Szabo G, Ruhparwar A, Kallenbach K, Karck M, Ehrlich JR, Baczko I, Borggrefe M, Ravens U, Dobrev D, Katus HA, Thomas D (2017) Inverse remodelling of K2P3.1 K+ channel expression and action potential duration in left ventricular dysfunction and atrial fibrillation: implications for patient-specific antiarrhythmic drug therapy. Eur Heart J 38:1764–1774. https://doi.org/10.1093/eurheartj/ehw559
Schmitt N, Grunnet M, Olesen SP (2014) Cardiac potassium channel subtypes: new roles in repolarization and arrhythmia. Physiol Rev 94:609–653. https://doi.org/10.1152/physrev.00022.2013
Scholz B, Schulte JS, Hamer S, Himmler K, Pluteanu F, Seidl MD, Stein J, Wardelmann E, Hammer E, Volker U, Muller FU (2019) HDAC (histone deacetylase) inhibitor valproic acid attenuates atrial remodeling and delays the onset of atrial fibrillation in mice. Circ Arrhythm Electrophysiol 12:e007071. https://doi.org/10.1161/CIRCEP.118.007071
Schweizer PA, Yampolsky P, Malik R, Thomas D, Zehelein J, Katus HA, Koenen M (2009) Transcription profiling of HCN-channel isotypes throughout mouse cardiac development. Basic Res Cardiol 104:621–629. https://doi.org/10.1007/s00395-009-0031-5
Seki M, LaCanna R, Powers JC, Vrakas C, Liu F, Berretta R, Chacko G, Holten J, Jadiya P, Wang T, Arkles JS, Copper JM, Houser SR, Huang J, Patel VV, Recchia FA (2016) Class I histone deacetylase inhibition for the treatment of sustained atrial fibrillation. J Pharmacol Exp Ther 358:441–449. https://doi.org/10.1124/jpet.116.234591
Shultz MD, Cao X, Chen CH, Cho YS, Davis NR, Eckman J, Fan J, Fekete A, Firestone B, Flynn J, Green J, Growney JD, Holmqvist M, Hsu M, Jansson D, Jiang L, Kwon P, Liu G, Lombardo F, Lu Q, Majumdar D, Meta C, Perez L, Pu M, Ramsey T, Remiszewski S, Skolnik S, Traebert M, Urban L, Uttamsingh V, Wang P, Whitebread S, Whitehead L, Yan-Neale Y, Yao YM, Zhou L, Atadja P (2011) Optimization of the in vitro cardiac safety of hydroxamate-based histone deacetylase inhibitors. J Med Chem 54:4752–4772. https://doi.org/10.1021/jm200388e
Tsai FC, Lin YC, Chang SH, Chang GJ, Hsu YJ, Lin YM, Lee YS, Wang CL, Yeh YH (2016) Differential left-to-right atria gene expression ratio in human sinus rhythm and atrial fibrillation: implications for arrhythmogenesis and thrombogenesis. Int J Cardiol 222:104–112. https://doi.org/10.1016/j.ijcard.2016.07.103
Zhang D, Wu CT, Qi X, Meijering RA, Hoogstra-Berends F, Tadevosyan A, Cubukcuoglu Deniz G, Durdu S, Akar AR, Sibon OC, Nattel S, Henning RH, Brundel BJ (2014) Activation of histone deacetylase-6 induces contractile dysfunction through derailment of alpha-tubulin proteostasis in experimental and human atrial fibrillation. Circulation 129:346–358. https://doi.org/10.1161/CIRCULATIONAHA.113.005300
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.
Author information
Authors and Affiliations
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
Ethics declarations
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).
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s00395-021-00855-x