Coordinated down-regulation of KCNQ1 and KCNE1 expression contributes to reduction of I(Ks) in canine hypertrophied hearts.
OBJECTIVE
In animal models of hypertrophy, electrical remodeling giving rise to QT prolongation occurs rapidly and is associated with the development of torsade de pointes (TdP) arrhythmias and sudden death. Chronic AV block (CAVB)-induced hypertrophy in dogs has been associated with a reduction in the slow component (I(Ks)) of the delayed rectifier potassium current (I(K)), which contributes to a prolongation of ventricular repolarization, the development of an acquired form of long QT, and the substrate for triggered activity and TdP. The present study was designed to probe the molecular basis for the decrease in I(Ks) by studying the characteristics of KCNE1 and KCNQ1, the putative genes responsible for formation of the channel.


RESULTS
Using a combination of Northern blot, competitive multiplex PCR and immunoblot assays, we found that CAVB reduces KCNE1 and KCNQ1 RNA in the canine ventricles by 70 and 80%, respectively. Protein levels of KCNE1 and KCNQ1 were reduced by 60 and 50%, respectively. We also demonstrate at the molecular level the basis for inter-ventricular difference in I(Ks) density previously reported in hearts of normal dogs and show the basis for reduction of this difference in the CAVB dog.


CONCLUSIONS
Our results indicate that the CAVB-induced reduction in I(Ks) is due to a down-regulation of KCNE1 and KCNQ1 transcription. The data suggest that electrical remodeling of the cardiac ventricle during hypertrophy involves regulation of the gene expression through modulation of transcriptional and translational regulatory pathways. The reduction in KCNE1 and KCNQ1 expression increases the dependence of ventricular repolarization on the rapid component of I(K) and may potentiate the action of Class III antiarrhythmic agents.
Ramakers
C
C
Cardiology, Cardiovascular Research Institute, Academic Hospital Maastricht, Maastricht, The Netherlands.
Vos
M A
MA
Doevendans
P A
PA
Schoenmakers
M
M
Wu
Y S
YS
Scicchitano
S
S
Iodice
A
A
Thomas
G P
GP
Antzelevitch
C
C
Dumaine
R
R
D000818:Animals; D015152:Blotting, Northern; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D004285:Dogs; D015536:Down-Regulation; D004594:Electrophysiology; D006327:Heart Block / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008133:Long QT Syndrome / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000235:genetics* / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D012313:RNA / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020257:Ventricular Remodeling
D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; C059983:potassium channel protein I(sk); D012313:RNA