Heart Rhythm
Volume 6, Issue 12 , Pages 1802-1809, December 2009

Changes in microRNA-1 expression and IK1 up-regulation in human atrial fibrillation

  • Zenawit Girmatsion, MSc

      Affiliations

    • Division of Cardiology, Goethe-University, Frankfurt, Germany
    • ,
  • Peter Biliczki, MD, PhD

      Affiliations

    • Division of Cardiology, Goethe-University, Frankfurt, Germany
    • ,
  • Angelika Bonauer, PhD

      Affiliations

    • Division of Cardiology, Goethe-University, Frankfurt, Germany
    • ,
  • Gerhard Wimmer-Greinecker, MD

      Affiliations

    • Department of Cardiothoracic Surgery, Goethe-University, Frankfurt, Germany
    • ,
  • Mirella Scherer, MD

      Affiliations

    • Department of Cardiothoracic Surgery, Goethe-University, Frankfurt, Germany
    • ,
  • Anton Moritz, MD

      Affiliations

    • Department of Cardiothoracic Surgery, Goethe-University, Frankfurt, Germany
    • ,
  • Alicia Bukowska, PhD

      Affiliations

    • Division of Cardiology, Otto-von-Guericke-University Hospital, Magdeburg, Germany
    • ,
  • Andreas Goette, MD

      Affiliations

    • Division of Cardiology, Otto-von-Guericke-University Hospital, Magdeburg, Germany
    • ,
  • Stanley Nattel, MD, FHRS

      Affiliations

    • Research Center, Montreal Heart Institute and Université de Montréal, Montreal, Canada
    • ,
  • Stefan H. Hohnloser, MD, FHRS

      Affiliations

    • Division of Cardiology, Goethe-University, Frankfurt, Germany
    • ,
  • Joachim R. Ehrlich, MD

      Affiliations

    • Division of Cardiology, Goethe-University, Frankfurt, Germany
    • Corresponding Author InformationAddress reprint requests and correspondence: Dr. Joachim R. Ehrlich, Division of Cardiology, Section of Electrophysiology, J. W. Goethe-Universität, Theodor Stern Kai 7, 60590 Frankfurt, Germany

Received 24 March 2009; accepted 28 August 2009. published online 07 September 2009.

Background

Atrial fibrillation (AF) is associated with increased inward-rectifier current activity that may stabilize atrial rotors maintaining the arrhythmia. Left atrial (LA) structures are important for AF maintenance, but previous studies have mostly evaluated changes in the right atrium. MicroRNA-1 (miR-1) reciprocally regulates inwardly rectifying potassium channel (Kir)2.1 expression in coronary disease, contributing to arrhythmogenesis.

Objectives

This study sought to evaluate changes in miR-1 and Kir2 subunit expression in relation to IK1 alterations in LA of patients with persistent AF.

Methods

Atrial tissue was obtained from 62 patients (31 with AF) undergoing mitral valve repair or bypass grafting. Currents were recorded from isolated cells. Proteins were quantified from immunoblots. mRNA and miR-1 levels were measured with real-time polymerase chain reaction. Immunohistochemistry was applied to localize connexin (Cx) 43.

Results

IK1 density was increased in LA cells from patients with AF (at −100 mV: −5.9 ± 1.3 vs. −2.7 ± 0.7 sinus rhythm, P <.05). There was a corresponding increase in Kir2.1 protein expression, but no change in other Kir or Cx proteins. Expression of inhibitory miR-1 was reduced by approximately 86% in tissue samples of AF patients. Kir2.1 mRNA was significantly increased. No change in Cx43 localization occurred. Ex vivo tachystimulation of human atrial slices up-regulated Kir2.1 and down-regulated miR-1, suggesting a primary role of atrial rate in miR-1 down-regulation and IK1 up-regulation.

Conclusion

miR-1 levels are greatly reduced in human AF, possibly contributing to up-regulation of Kir2.1 subunits, leading to increased IK1. Because up-regulation of inward-rectifier currents is important for AF maintenance, these results provide potential new insights into molecular mechanisms of AF with potential therapeutic implications.

Keywords: Inward rectifier potassium currents, IKACh, IK1, connexin, atrial fibrillation, microRNA

Abbreviations: AF, atrial fibrillation, BSA, bovine serum albumin, CAD, coronary artery disease, Cx, connexin, DTT, dithiothreitol, GAPDH, glyceraldehyde 3-phosphate dehydrogenase, LA, left atrial, miR-1, microRNA 1, PCR, polymerase chain reaction, RT, reverse transcription, SR, sinus rhythm, TTBS, Tris-Tween buffered solution

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 Dr. Ehrlich received support from Hans und Gertie Fischer–Stiftung and Adolf Messer–Stiftung. Dr Nattel was supported by the Canadian Institutes of Health Research (MOP 44365). Dr. Biliczki was the recipient of a postdoctoral fellowship of the Deutsche Gesellschaft für Kardiologie. Mrs. Girmatsion received an award from the August Scheidel–Stiftung.

 Drs. Girmatsion and Biliczki contributed equally to this work.

 The authors thank Sabine Harenkamp for expert technical assistance.

PII: S1547-5271(09)00984-9

doi:10.1016/j.hrthm.2009.08.035

Heart Rhythm
Volume 6, Issue 12 , Pages 1802-1809, December 2009

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