Epigenetic regulation of cardiac electrophysiology in atrial fibrillation: HDAC2 determines action potential duration and suppresses NRSF in cardiomyocytes
- 25 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Basic Research in Cardiology
- Vol. 116 (1), 1-11
- https://doi.org/10.1007/s00395-021-00855-x
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.Keywords
Funding Information
- University of Heidelberg, Faculty of Medicine (Postdoctoral Fellowships, Postdoctoral Fellowship)
- Deutsche Gesellschaft für Kardiologie-Herz und Kreislaufforschung. (Fellowship, Fellowship, Otto-Hess-Promotionsstipendium)
- Ernst und Berta Grimmke Stiftung
- Elisabeth und Rudolf-Hirsch Stiftung für Medizinische Forschung
- Deutsche Stiftung für Herzforschung (F/08/14, Fellowship, Kaltenbach-Promotionsstipendium, Kaltenbach-Promotionsstipendium, Kaltenbach-Promotionsstipendium)
- German Internal Medicine Society (Clinician-Scientist-Program)
- Joachim Siebeneicher Foundation
- Deutsche Forschungsgemeinschaft (SCHW 1611/-1, TH 1120/7-1, TH 1120/8-1)
- Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg (Sonderlinie Medizin)
- Heidelberg Research Center for Molecular Medicine (Senior Career Fellowship)
- Department of Cardiology, University of Heidelberg (Cardiology Career Program, Cardiology Career Program)
This publication has 35 references indexed in Scilit:
- Spatial gradients in action potential duration created by regional magnetofection of hERG are a substrate for wavebreak and turbulent propagation in cardiomyocyte monolayersJournal Of Physiology-London, 2012
- Optimization of the in Vitro Cardiac Safety of Hydroxamate-Based Histone Deacetylase InhibitorsJournal of Medicinal Chemistry, 2011
- Lysine Acetylation Targets Protein Complexes and Co-Regulates Major Cellular FunctionsScience, 2009
- Transcription profiling of HCN-channel isotypes throughout mouse cardiac developmentBasic Research in Cardiology, 2009
- Histone-deacetylase inhibition reverses atrial arrhythmia inducibility and fibrosis in cardiac hypertrophy independent of angiotensinJournal of Molecular and Cellular Cardiology, 2008
- Atrial Fibrosis: Mechanisms and Clinical Relevance in Atrial FibrillationJournal of the American College of Cardiology, 2008
- Histone deacetylases 1 and 2 redundantly regulate cardiac morphogenesis, growth, and contractilityGenes & Development, 2007
- Arrhythmogenic Ion-Channel Remodeling in the Heart: Heart Failure, Myocardial Infarction, and Atrial FibrillationPhysiological Reviews, 2007
- Suppression of Class I and II Histone Deacetylases Blunts Pressure-Overload Cardiac HypertrophyCirculation, 2006
- Molecular Evolution of the Histone Deacetylase Family: Functional Implications of Phylogenetic AnalysisJournal of Molecular Biology, 2004