Differential regulation of KCa2.1 (KCNN1) K+ channel expression by histone deacetylases in atrial fibrillation with concomitant heart failure
Atrial fibrillation (AF) with concomitant heart failure (HF) poses a significant therapeutic challenge. Mechanism‐based approaches may optimize AF therapy. Small‐conductance, calcium‐activated K+ (KCa, KCNN) channels contribute to cardiac action potential repolarization. KCNN1 exhibits predominant a...
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Published in | Physiological reports Vol. 9; no. 11 |
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Main Authors | , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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Oxford
John Wiley & Sons, Inc
01.06.2021
John Wiley and Sons Inc Wiley |
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Abstract | Atrial fibrillation (AF) with concomitant heart failure (HF) poses a significant therapeutic challenge. Mechanism‐based approaches may optimize AF therapy. Small‐conductance, calcium‐activated K+ (KCa, KCNN) channels contribute to cardiac action potential repolarization. KCNN1 exhibits predominant atrial expression and is downregulated in chronic AF patients with preserved cardiac function. Epigenetic regulation is suggested by AF suppression following histone deacetylase (HDAC) inhibition. We hypothesized that HDAC‐dependent KCNN1 remodeling contributes to arrhythmogenesis in AF complicated by HF. The aim of this study was to assess KCNN1 and HDAC1–7 and 9 transcript levels in AF/HF patients and in a pig model of atrial tachypacing‐induced AF with reduced left ventricular function. In HL‐1 atrial myocytes, tachypacing and anti‐Hdac siRNAs were employed to investigate effects on Kcnn1 mRNA levels. KCNN1 expression displayed side‐specific remodeling in AF/HF patients with upregulation in left and suppression in right atrium. In pigs, KCNN1 remodeling showed intermediate phenotypes. HDAC levels were differentially altered in humans and pigs, reflecting highly variable epigenetic regulation. Tachypacing recapitulated downregulation of Hdacs 1, 3, 4, 6, and 7 with a tendency towards reduced Kcnn1 levels in vitro, indicating that atrial high rates induce remodeling. Finally, Kcnn1 expression was decreased by knockdown of Hdacs 2, 3, 6, and 7 and enhanced by genetic Hdac9 inactivation, while anti‐Hdac 1, 4, and 5 siRNAs did not affect Kcnn1 transcript levels. In conclusion, KCNN1 and HDAC expression is differentially remodeled in AF complicated by HF. Direct regulation of KCNN1 by HDACs in atrial myocytes provides a basis for mechanism‐based antiarrhythmic therapy.
Atrial KCNN1 channels are remodeled in patients and pigs with atrial fibrillation. KCNN1 remodeling is associated with changes in histone deacetylase (HDAC) expression: Inactivation of Hdac9 enhances Kcnn1, Knock‐down of Hdacs 2, 3, 6, and 7 suppresses Kcnn1. KCNN1 regulation by HDACs serves a basis for mechanism‐based antiarrhythmic therapy. |
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AbstractList | Abstract Atrial fibrillation (AF) with concomitant heart failure (HF) poses a significant therapeutic challenge. Mechanism‐based approaches may optimize AF therapy. Small‐conductance, calcium‐activated K+ (KCa, KCNN) channels contribute to cardiac action potential repolarization. KCNN1 exhibits predominant atrial expression and is downregulated in chronic AF patients with preserved cardiac function. Epigenetic regulation is suggested by AF suppression following histone deacetylase (HDAC) inhibition. We hypothesized that HDAC‐dependent KCNN1 remodeling contributes to arrhythmogenesis in AF complicated by HF. The aim of this study was to assess KCNN1 and HDAC1–7 and 9 transcript levels in AF/HF patients and in a pig model of atrial tachypacing‐induced AF with reduced left ventricular function. In HL‐1 atrial myocytes, tachypacing and anti‐Hdac siRNAs were employed to investigate effects on Kcnn1 mRNA levels. KCNN1 expression displayed side‐specific remodeling in AF/HF patients with upregulation in left and suppression in right atrium. In pigs, KCNN1 remodeling showed intermediate phenotypes. HDAC levels were differentially altered in humans and pigs, reflecting highly variable epigenetic regulation. Tachypacing recapitulated downregulation of Hdacs 1, 3, 4, 6, and 7 with a tendency towards reduced Kcnn1 levels in vitro, indicating that atrial high rates induce remodeling. Finally, Kcnn1 expression was decreased by knockdown of Hdacs 2, 3, 6, and 7 and enhanced by genetic Hdac9 inactivation, while anti‐Hdac 1, 4, and 5 siRNAs did not affect Kcnn1 transcript levels. In conclusion, KCNN1 and HDAC expression is differentially remodeled in AF complicated by HF. Direct regulation of KCNN1 by HDACs in atrial myocytes provides a basis for mechanism‐based antiarrhythmic therapy. Atrial fibrillation (AF) with concomitant heart failure (HF) poses a significant therapeutic challenge. Mechanism‐based approaches may optimize AF therapy. Small‐conductance, calcium‐activated K+ (KCa, KCNN) channels contribute to cardiac action potential repolarization. KCNN1 exhibits predominant atrial expression and is downregulated in chronic AF patients with preserved cardiac function. Epigenetic regulation is suggested by AF suppression following histone deacetylase (HDAC) inhibition. We hypothesized that HDAC‐dependent KCNN1 remodeling contributes to arrhythmogenesis in AF complicated by HF. The aim of this study was to assess KCNN1 and HDAC1–7 and 9 transcript levels in AF/HF patients and in a pig model of atrial tachypacing‐induced AF with reduced left ventricular function. In HL‐1 atrial myocytes, tachypacing and anti‐Hdac siRNAs were employed to investigate effects on Kcnn1 mRNA levels. KCNN1 expression displayed side‐specific remodeling in AF/HF patients with upregulation in left and suppression in right atrium. In pigs, KCNN1 remodeling showed intermediate phenotypes. HDAC levels were differentially altered in humans and pigs, reflecting highly variable epigenetic regulation. Tachypacing recapitulated downregulation of Hdacs 1, 3, 4, 6, and 7 with a tendency towards reduced Kcnn1 levels in vitro, indicating that atrial high rates induce remodeling. Finally, Kcnn1 expression was decreased by knockdown of Hdacs 2, 3, 6, and 7 and enhanced by genetic Hdac9 inactivation, while anti‐Hdac 1, 4, and 5 siRNAs did not affect Kcnn1 transcript levels. In conclusion, KCNN1 and HDAC expression is differentially remodeled in AF complicated by HF. Direct regulation of KCNN1 by HDACs in atrial myocytes provides a basis for mechanism‐based antiarrhythmic therapy. Atrial fibrillation (AF) with concomitant heart failure (HF) poses a significant therapeutic challenge. Mechanism‐based approaches may optimize AF therapy. Small‐conductance, calcium‐activated K+ (KCa, KCNN) channels contribute to cardiac action potential repolarization. KCNN1 exhibits predominant atrial expression and is downregulated in chronic AF patients with preserved cardiac function. Epigenetic regulation is suggested by AF suppression following histone deacetylase (HDAC) inhibition. We hypothesized that HDAC‐dependent KCNN1 remodeling contributes to arrhythmogenesis in AF complicated by HF. The aim of this study was to assess KCNN1 and HDAC1–7 and 9 transcript levels in AF/HF patients and in a pig model of atrial tachypacing‐induced AF with reduced left ventricular function. In HL‐1 atrial myocytes, tachypacing and anti‐Hdac siRNAs were employed to investigate effects on Kcnn1 mRNA levels. KCNN1 expression displayed side‐specific remodeling in AF/HF patients with upregulation in left and suppression in right atrium. In pigs, KCNN1 remodeling showed intermediate phenotypes. HDAC levels were differentially altered in humans and pigs, reflecting highly variable epigenetic regulation. Tachypacing recapitulated downregulation of Hdacs 1, 3, 4, 6, and 7 with a tendency towards reduced Kcnn1 levels in vitro, indicating that atrial high rates induce remodeling. Finally, Kcnn1 expression was decreased by knockdown of Hdacs 2, 3, 6, and 7 and enhanced by genetic Hdac9 inactivation, while anti‐Hdac 1, 4, and 5 siRNAs did not affect Kcnn1 transcript levels. In conclusion, KCNN1 and HDAC expression is differentially remodeled in AF complicated by HF. Direct regulation of KCNN1 by HDACs in atrial myocytes provides a basis for mechanism‐based antiarrhythmic therapy. Atrial KCNN1 channels are remodeled in patients and pigs with atrial fibrillation. KCNN1 remodeling is associated with changes in histone deacetylase (HDAC) expression: Inactivation of Hdac9 enhances Kcnn1, Knock‐down of Hdacs 2, 3, 6, and 7 suppresses Kcnn1. KCNN1 regulation by HDACs serves a basis for mechanism‐based antiarrhythmic therapy. Atrial fibrillation (AF) with concomitant heart failure (HF) poses a significant therapeutic challenge. Mechanism‐based approaches may optimize AF therapy. Small‐conductance, calcium‐activated K + (K Ca , KCNN ) channels contribute to cardiac action potential repolarization. KCNN1 exhibits predominant atrial expression and is downregulated in chronic AF patients with preserved cardiac function. Epigenetic regulation is suggested by AF suppression following histone deacetylase (HDAC) inhibition. We hypothesized that HDAC‐dependent KCNN1 remodeling contributes to arrhythmogenesis in AF complicated by HF. The aim of this study was to assess KCNN1 and HDAC1–7 and 9 transcript levels in AF/HF patients and in a pig model of atrial tachypacing‐induced AF with reduced left ventricular function. In HL‐1 atrial myocytes, tachypacing and anti‐ Hdac siRNAs were employed to investigate effects on Kcnn1 mRNA levels. KCNN1 expression displayed side‐specific remodeling in AF/HF patients with upregulation in left and suppression in right atrium. In pigs, KCNN1 remodeling showed intermediate phenotypes. HDAC levels were differentially altered in humans and pigs, reflecting highly variable epigenetic regulation. Tachypacing recapitulated downregulation of Hdacs 1 , 3 , 4 , 6 , and 7 with a tendency towards reduced Kcnn1 levels in vitro, indicating that atrial high rates induce remodeling. Finally, Kcnn1 expression was decreased by knockdown of Hdacs 2 , 3 , 6 , and 7 and enhanced by genetic Hdac9 inactivation, while anti‐ Hdac 1 , 4 , and 5 siRNAs did not affect Kcnn1 transcript levels. In conclusion, KCNN1 and HDAC expression is differentially remodeled in AF complicated by HF. Direct regulation of KCNN1 by HDACs in atrial myocytes provides a basis for mechanism‐based antiarrhythmic therapy. Atrial KCNN1 channels are remodeled in patients and pigs with atrial fibrillation. KCNN1 remodeling is associated with changes in histone deacetylase (HDAC) expression: Inactivation of Hdac9 enhances Kcnn1, Knock‐down of Hdacs 2, 3, 6, and 7 suppresses Kcnn1. KCNN1 regulation by HDACs serves a basis for mechanism‐based antiarrhythmic therapy. |
Author | Gramlich, Dominik Most, Patrick Thomas, Dierk Weis, Tanja Rahm, Ann‐Kathrin Wunsch, Maximilian N. Sandke, Steffi Lugenbiel, Patrick Müller, Mara Elena Wieder, Teresa Katus, Hugo A. Heimberger, Tanja El Tahry, Fadwa A. |
AuthorAffiliation | 1 Department of Cardiology Medical University Hospital Heidelberg Heidelberg Germany 3 DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim University of Heidelberg Heidelberg Germany 2 HCR (Heidelberg Center for Heart Rhythm Disorders) University Hospital Heidelberg Heidelberg Germany |
AuthorAffiliation_xml | – name: 3 DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim University of Heidelberg Heidelberg Germany – name: 1 Department of Cardiology Medical University Hospital Heidelberg Heidelberg Germany – name: 2 HCR (Heidelberg Center for Heart Rhythm Disorders) University Hospital Heidelberg Heidelberg Germany |
Author_xml | – sequence: 1 givenname: Ann‐Kathrin orcidid: 0000-0002-7509-887X surname: Rahm fullname: Rahm, Ann‐Kathrin organization: University of Heidelberg – sequence: 2 givenname: Teresa surname: Wieder fullname: Wieder, Teresa organization: University Hospital Heidelberg – sequence: 3 givenname: Dominik surname: Gramlich fullname: Gramlich, Dominik organization: University of Heidelberg – sequence: 4 givenname: Mara Elena surname: Müller fullname: Müller, Mara Elena organization: University of Heidelberg – sequence: 5 givenname: Maximilian N. surname: Wunsch fullname: Wunsch, Maximilian N. organization: University of Heidelberg – sequence: 6 givenname: Fadwa A. surname: El Tahry fullname: El Tahry, Fadwa A. organization: University of Heidelberg – sequence: 7 givenname: Tanja surname: Heimberger fullname: Heimberger, Tanja organization: University of Heidelberg – sequence: 8 givenname: Steffi surname: Sandke fullname: Sandke, Steffi organization: University of Heidelberg – sequence: 9 givenname: Tanja surname: Weis fullname: Weis, Tanja organization: University of Heidelberg – sequence: 10 givenname: Patrick surname: Most fullname: Most, Patrick organization: University Hospital Heidelberg – sequence: 11 givenname: Hugo A. surname: Katus fullname: Katus, Hugo A. organization: University of Heidelberg – sequence: 12 givenname: Dierk orcidid: 0000-0002-5687-7843 surname: Thomas fullname: Thomas, Dierk email: dierk.thomas@med.uni-heidelberg.de organization: University of Heidelberg – sequence: 13 givenname: Patrick surname: Lugenbiel fullname: Lugenbiel, Patrick organization: University of Heidelberg |
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Notes | Funding information This work was funded in part by research grants from the University of Heidelberg, Faculty of Medicine (Postdoctoral Fellowships to P.L. and A.K.R.), from the German Cardiac Society (Fellowships to A.K.R. and P.L., Otto‐Hess‐Promotionsstipendium to D.G.), from the Elisabeth und Rudolf‐Hirsch Stiftung für Medizinische Forschung (to A.K.R.), from the Ernst und Berta Grimmke‐Stiftung (to P.L.), from the German Heart Foundation/German Foundation of Heart Research (F/08/14 to D.T., Fellowship to A.K.R., Kaltenbach‐Promotionsstipendium to 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; 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.). D.G., T.W., and M.E.M. were supported by the Cardiology Career Program of the Department of Cardiology, University of Heidelberg, and D.G. received a scholarship from the German Academic Scholarship Foundation. The funding sources had no involvement in study design; in the collection, analysis and interpretation of data; and in the decision to submit the article for publication. |
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References | 2015; 12 2013; 4 2010; 107 2021; 266 2013; 24 2019; 12 2015; 10 2020; 127 2019; 105 2010; 285 2016; 781 2011; 57 2013; 384 2007; 75 2017; 112 2003; 278 2013; 6 2014; 114 2018; 49 2016; 13 2018; 24 2007; 16 2014; 129 2016; 5 2018; 9 2012; 90 2011; 108 2015; 290 2013; 10 2017; 38 2005; 289 2021; 116 2011; 51 2015; 132 2016; 311 2016; 20 2016; 358 2010; 3 2009; 587 2014; 103 2014; 101 |
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Snippet | Atrial fibrillation (AF) with concomitant heart failure (HF) poses a significant therapeutic challenge. Mechanism‐based approaches may optimize AF therapy.... Abstract Atrial fibrillation (AF) with concomitant heart failure (HF) poses a significant therapeutic challenge. Mechanism‐based approaches may optimize AF... |
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SubjectTerms | Action potential atrial fibrillation Calcium conductance Cardiac arrhythmia Cardiomyopathy Cardiovascular disease Congestive heart failure Ejection fraction electrophysiology Epigenetics Ethics Experiments Fibrillation Gene expression Heart failure Histone deacetylase KCa channel Laboratory animals Myocytes Original Patients Phenotypes Physiology Potassium channels (calcium-gated) Potassium conductance Proteins siRNA Transcription Ventricle |
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Title | Differential regulation of KCa2.1 (KCNN1) K+ channel expression by histone deacetylases in atrial fibrillation with concomitant heart failure |
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