Molecular mechanisms of early electrical remodeling: transcriptional downregulation of ion channel subunits reduces I(Ca,L) and I(to) in rapid atrial pacing in rabbits.
OBJECTIVE
The purpose of the study was to characterize the ionic and molecular mechanisms in the very early phases of electrical remodeling in a rabbit model of rapid atrial pacing (RAP).


BACKGROUND
Long-term atrial fibrillation reduces L-type Ca(2+) (I(Ca,L)) and transient outward K(+) (I(to)) currents by transcriptional downregulation of the underlying ionic channels. However, electrical remodeling starts early after the onset of rapid atrial rates. The time course of ion current and channel modulation in these early phases of remodeling is currently unknown.


METHODS
Rapid (600 beats/min) right atrial pacing was performed in rabbits. Animals were divided into five groups with pacing durations between 0 and 96 h. Ionic currents were measured by patch clamp techniques; messenger ribonucleic acid (mRNA) and protein expression were measured by reverse transcription-polymerase chain reaction and Western blot, respectively.


RESULTS
L-type calcium current started to be reduced (by 47%) after 12 h of RAP and continued to decline as pacing continued. Current changes were preceded or paralleled by decreased mRNA expression of the Ca(2+) channel beta subunits CaB2a, CaB2b, and CaB3, whereas significant reductions in the alpha(1) subunit mRNA and protein expression began 24 h after pacing onset. Transient outward potassium current densities were not altered within the first 12 h, but after 24 h, currents were reduced by 48%. Longer pacing periods did not further decrease I(to). Current changes were paralleled by reduced Kv4.3 mRNA expression. Kv4.2, Kv1.4, and the auxiliary subunit KChIP2 were not affected.


CONCLUSIONS
L-type calcium current and I(to) are reduced in early phases of electrical remodeling. A major mechanism appears to be transcriptional downregulation of underlying ion channels, which partially preceded ion current changes.
Bosch
Ralph F
RF
Department of Cardiology, University of Tübingen, Tübingen, Germany. ralph.bosch@uni-tuebingen.de
Scherer
Constanze R
CR
Rüb
Norman
N
Wöhrl
Stefan
S
Steinmeyer
Klaus
K
Haase
Hannelore
H
Busch
Andreas E
AE
Seipel
Ludger
L
Kühlkamp
Volker
V
D000704:Analysis of Variance; D000818:Animals; D001281:Atrial Fibrillation / Q000473:pathology / Q000628:therapy*; D001483:Base Sequence; D015153:Blotting, Western; D020746:Calcium Channels, L-Type / Q000032:analysis / Q000378:metabolism*; D002304:Cardiac Pacing, Artificial; D004195:Disease Models, Animal; D015536:Down-Regulation; D004553:Electric Conductivity; D004594:Electrophysiology; D005260:Female; D017136:Ion Transport / Q000502:physiology*; D008297:Male; D008969:Molecular Sequence Data; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000032:analysis / Q000378:metabolism*; D011336:Probability; D012333:RNA, Messenger / Q000032:analysis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity
D020746:Calcium Channels, L-Type; D015221:Potassium Channels; D012333:RNA, Messenger