title: Fibroblast inward-rectifier potassium current upregulation in profibrillatory atrial remodeling.
abstract: BACKGROUND
  Fibroblasts are involved in cardiac arrhythmogenesis and contribute to the atrial fibrillation substrate in congestive heart failure (CHF) by generating tissue fibrosis. Fibroblasts display robust ion currents, but their functional importance is poorly understood.
  
  
  OBJECTIVE
  To characterize atrial fibroblast inward-rectifier K(+) current (IK1) remodeling in CHF and its effects on fibroblast properties.
  
  
  RESULTS
  Freshly isolated left atrial fibroblasts were obtained from controls and dogs with CHF (ventricular tachypacing). Patch clamp was used to record resting membrane potential (RMP) and IK1. RMP was significantly increased by CHF (from -43.2±0.8 mV, control, to -55.5±0.9 mV). CHF upregulated IK1 (eg, at -90 mV from -1.1±0.2 to -2.7±0.5 pA/pF) and increased the expression of KCNJ2 mRNA (by 52%) and protein (by 80%). Ba(2+) (300 μmol/L) decreased the RMP and suppressed the RMP difference between controls and dogs with CHF. Store-operated Ca(2+) entry (Fura-2-acetoxymethyl ester) and fibroblast proliferation (flow cytometry) were enhanced by CHF. Lentivirus-mediated overexpression of KCNJ2 enhanced IK1 and hyperpolarized fibroblasts. Functional KCNJ2 suppression by lentivirus-mediated expression of a dominant negative KCNJ2 construct suppressed IK1 and depolarized RMP. Overexpression of KCNJ2 increased Ca(2+) entry and fibroblast proliferation, whereas the dominant negative KCNJ2 construct had opposite effects. Fibroblast hyperpolarization to mimic CHF effects on RMP enhanced the Ca(2+) entry. MicroRNA-26a, which targets KCNJ2, was downregulated in CHF fibroblasts. Knockdown of endogenous microRNA-26 to mimic CHF effects unregulated IK1.
  
  
  CONCLUSIONS
  CHF upregulates fibroblast KCNJ2 expression and currents, thereby hyperpolarizing RMP, increasing Ca(2+) entry, and enhancing atrial fibroblast proliferation. These effects are likely mediated by microRNA-26a downregulation. Remodeling-induced fibroblast KCNJ2 expression changes may play a role in atrial fibrillation promoting fibroblast remodeling and structural/arrhythmic consequences.
authors.affiliation: From the Research Center and Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada (X.-Y.Q., H.H., B.O., X.L., P.N., Y.S., C.-T.W., K.D., A.T., Y.C., M.H., S.N.); Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada (K.D., Y.C.); Department of Cardiology, Chang-Gung Memorial Hospital and University, Taoyuan, Taiwan, Republic of China (C.T.W., S.N.); Department of Cardiology, Fujita Health University School of Medicine, Toyoake, Japan (M.H.); and Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (D.D.).
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Qi
authors.affiliation: From the Research Center and Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada (X.-Y.Q., H.H., B.O., X.L., P.N., Y.S., C.-T.W., K.D., A.T., Y.C., M.H., S.N.); Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada (K.D., Y.C.); Department of Cardiology, Chang-Gung Memorial Hospital and University, Taoyuan, Taiwan, Republic of China (C.T.W., S.N.); Department of Cardiology, Fujita Health University School of Medicine, Toyoake, Japan (M.H.); and Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (D.D.).
authors.forename: Hai
authors.initials: H
authors.lastname: Huang
authors.affiliation: From the Research Center and Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada (X.-Y.Q., H.H., B.O., X.L., P.N., Y.S., C.-T.W., K.D., A.T., Y.C., M.H., S.N.); Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada (K.D., Y.C.); Department of Cardiology, Chang-Gung Memorial Hospital and University, Taoyuan, Taiwan, Republic of China (C.T.W., S.N.); Department of Cardiology, Fujita Health University School of Medicine, Toyoake, Japan (M.H.); and Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (D.D.).
authors.forename: Balazs
authors.initials: B
authors.lastname: Ordog
authors.affiliation: From the Research Center and Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada (X.-Y.Q., H.H., B.O., X.L., P.N., Y.S., C.-T.W., K.D., A.T., Y.C., M.H., S.N.); Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada (K.D., Y.C.); Department of Cardiology, Chang-Gung Memorial Hospital and University, Taoyuan, Taiwan, Republic of China (C.T.W., S.N.); Department of Cardiology, Fujita Health University School of Medicine, Toyoake, Japan (M.H.); and Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (D.D.).
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Luo
authors.affiliation: From the Research Center and Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada (X.-Y.Q., H.H., B.O., X.L., P.N., Y.S., C.-T.W., K.D., A.T., Y.C., M.H., S.N.); Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada (K.D., Y.C.); Department of Cardiology, Chang-Gung Memorial Hospital and University, Taoyuan, Taiwan, Republic of China (C.T.W., S.N.); Department of Cardiology, Fujita Health University School of Medicine, Toyoake, Japan (M.H.); and Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (D.D.).
authors.forename: Patrice
authors.initials: P
authors.lastname: Naud
authors.affiliation: From the Research Center and Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada (X.-Y.Q., H.H., B.O., X.L., P.N., Y.S., C.-T.W., K.D., A.T., Y.C., M.H., S.N.); Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada (K.D., Y.C.); Department of Cardiology, Chang-Gung Memorial Hospital and University, Taoyuan, Taiwan, Republic of China (C.T.W., S.N.); Department of Cardiology, Fujita Health University School of Medicine, Toyoake, Japan (M.H.); and Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (D.D.).
authors.forename: Yiguo
authors.initials: Y
authors.lastname: Sun
authors.affiliation: From the Research Center and Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada (X.-Y.Q., H.H., B.O., X.L., P.N., Y.S., C.-T.W., K.D., A.T., Y.C., M.H., S.N.); Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada (K.D., Y.C.); Department of Cardiology, Chang-Gung Memorial Hospital and University, Taoyuan, Taiwan, Republic of China (C.T.W., S.N.); Department of Cardiology, Fujita Health University School of Medicine, Toyoake, Japan (M.H.); and Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (D.D.).
authors.forename: Chia-Tung
authors.initials: CT
authors.lastname: Wu
authors.affiliation: From the Research Center and Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada (X.-Y.Q., H.H., B.O., X.L., P.N., Y.S., C.-T.W., K.D., A.T., Y.C., M.H., S.N.); Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada (K.D., Y.C.); Department of Cardiology, Chang-Gung Memorial Hospital and University, Taoyuan, Taiwan, Republic of China (C.T.W., S.N.); Department of Cardiology, Fujita Health University School of Medicine, Toyoake, Japan (M.H.); and Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (D.D.).
authors.forename: Kristin
authors.initials: K
authors.lastname: Dawson
authors.affiliation: From the Research Center and Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada (X.-Y.Q., H.H., B.O., X.L., P.N., Y.S., C.-T.W., K.D., A.T., Y.C., M.H., S.N.); Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada (K.D., Y.C.); Department of Cardiology, Chang-Gung Memorial Hospital and University, Taoyuan, Taiwan, Republic of China (C.T.W., S.N.); Department of Cardiology, Fujita Health University School of Medicine, Toyoake, Japan (M.H.); and Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (D.D.).
authors.forename: Artavazd
authors.initials: A
authors.lastname: Tadevosyan
authors.affiliation: From the Research Center and Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada (X.-Y.Q., H.H., B.O., X.L., P.N., Y.S., C.-T.W., K.D., A.T., Y.C., M.H., S.N.); Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada (K.D., Y.C.); Department of Cardiology, Chang-Gung Memorial Hospital and University, Taoyuan, Taiwan, Republic of China (C.T.W., S.N.); Department of Cardiology, Fujita Health University School of Medicine, Toyoake, Japan (M.H.); and Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (D.D.).
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: From the Research Center and Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada (X.-Y.Q., H.H., B.O., X.L., P.N., Y.S., C.-T.W., K.D., A.T., Y.C., M.H., S.N.); Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada (K.D., Y.C.); Department of Cardiology, Chang-Gung Memorial Hospital and University, Taoyuan, Taiwan, Republic of China (C.T.W., S.N.); Department of Cardiology, Fujita Health University School of Medicine, Toyoake, Japan (M.H.); and Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (D.D.).
authors.forename: Masahide
authors.initials: M
authors.lastname: Harada
authors.affiliation: From the Research Center and Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada (X.-Y.Q., H.H., B.O., X.L., P.N., Y.S., C.-T.W., K.D., A.T., Y.C., M.H., S.N.); Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada (K.D., Y.C.); Department of Cardiology, Chang-Gung Memorial Hospital and University, Taoyuan, Taiwan, Republic of China (C.T.W., S.N.); Department of Cardiology, Fujita Health University School of Medicine, Toyoake, Japan (M.H.); and Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (D.D.).
authors.forename: Dobromir
authors.initials: D
authors.lastname: Dobrev
authors.affiliation: From the Research Center and Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada (X.-Y.Q., H.H., B.O., X.L., P.N., Y.S., C.-T.W., K.D., A.T., Y.C., M.H., S.N.); Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada (K.D., Y.C.); Department of Cardiology, Chang-Gung Memorial Hospital and University, Taoyuan, Taiwan, Republic of China (C.T.W., S.N.); Department of Cardiology, Fujita Health University School of Medicine, Toyoake, Japan (M.H.); and Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (D.D.). stanley.nattel@icm-mhi.org.
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D064752:Atrial Remodeling / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002304:Cardiac Pacing, Artificial; D002453:Cell Cycle; D002455:Cell Division; D004285:Dogs; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006333:Heart Failure / Q000150:complications* / Q000503:physiopathology; D017136:Ion Transport; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014161:Transduction, Genetic; D015854:Up-Regulation
chemical_list: C489461:Kir2.1 channel; D035683:MicroRNAs; D024661:Potassium Channels, Inwardly Rectifying; D011993:Recombinant Fusion Proteins; D011188:Potassium; D002118:Calcium
keywords: arrhythmias, cardiac