Molecular basis of transient outward potassium current downregulation in human heart failure: a decrease in Kv4.3 mRNA correlates with a reduction in current density.
BACKGROUND
Despite advances in medical therapy, congestive heart failure remains a major cause of death in the developed world. A disproportionate number of the deaths of patients with heart failure are sudden and presumed to be arrhythmic. Heart failure in humans and in animal models is associated with prolongation of the action potential duration (APD), the result of downregulation of K+ currents-prominently, the Ca2+-independent transient outward current (Ito). The mechanism for the reduction of Ito in heart failure is unknown. The K+ channel alpha-subunit Kv4.3, a homolog of the Drosophila Shal family, is most likely to encode all or part of the native cardiac Ito in humans.


RESULTS
We used ribonuclease protection assays and whole-cell electrophysiological recording to study changes in the level of Kv4.3 mRNA and Ito in human tissues and isolated ventricular myocytes, respectively. We found that the level of Kv4.3 mRNA decreased by 30% in failing hearts compared with nonfailing controls. Furthermore, this reduction correlated with the reduction in peak Ito density measured in ventricular myocytes isolated from adjacent regions of the heart. There was no significant change in the steady-state level of any other mRNA studied (HERG, Kv1.4, Kir2.1, Kvss1.3, and the alpha1C subunit of the Ca2+ channel). mRNAs encoding Kv1.2, Kv1.5, and Kv2.1 were found in low abundance in human ventricle.


CONCLUSIONS
These data provide further support for the hypothesis that Kv4.3 encodes all or part of the native cardiac Ito in humans and that part of the downregulation of this current in heart failure may be transcriptionally regulated.
Kääb
S
S
Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Dixon
J
J
Duc
J
J
Ashen
D
D
Näbauer
M
M
Beuckelmann
D J
DJ
Steinbeck
G
G
McKinnon
D
D
Tomaselli
G F
GF
D000200:Action Potentials / Q000502:physiology; D000328:Adult; D000368:Aged; D015220:Calcium Channels / Q000235:genetics; D027682:Cation Transport Proteins; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D016757:Death, Sudden, Cardiac / Q000209:etiology; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D006333:Heart Failure / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D016027:Heart Transplantation; D006352:Heart Ventricles / Q000473:pathology; D006801:Humans; D017136:Ion Transport; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D009206:Myocardium / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism*; D015221:Potassium Channels / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D051672:Shal Potassium Channels; D015534:Trans-Activators; D014158:Transcription, Genetic; D000071230:Transcriptional Regulator ERG
D015220:Calcium Channels; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C497021:KCND3 protein, human; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D009124:Muscle Proteins; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger; D051672:Shal Potassium Channels; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D011188:Potassium