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


OBJECTIVE
This study sought to evaluate changes in miR-1 and Kir2 subunit expression in relation to I(K1) 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
I(K1) 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 I(K1) up-regulation.


CONCLUSIONS
miR-1 levels are greatly reduced in human AF, possibly contributing to up-regulation of Kir2.1 subunits, leading to increased I(K1). 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.
Girmatsion
Zenawit
Z
Division of Cardiology, Goethe-University, Frankfurt, Germany.
Biliczki
Peter
P
Bonauer
Angelika
A
Wimmer-Greinecker
Gerhard
G
Scherer
Mirella
M
Moritz
Anton
A
Bukowska
Alicia
A
Goette
Andreas
A
Nattel
Stanley
S
Hohnloser
Stefan H
SH
Ehrlich
Joachim R
JR
D000200:Action Potentials; D000368:Aged; D001281:Atrial Fibrillation / Q000235:genetics / Q000378:metabolism*; D017630:Connexins / Q000378:metabolism; D004594:Electrophysiology; D005260:Female; D006325:Heart Atria / Q000378:metabolism*; D006801:Humans; D015640:Ion Channel Gating; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D017630:Connexins; D035683:MicroRNAs; D024661:Potassium Channels, Inwardly Rectifying