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

Autor: Stefan Kääb, D. Ashen, Gordon F. Tomaselli, J. Duc, Michael Nabauer, Dirk J. Beuckelmann, David McKinnon, Jane E. Dixon, Gerhard Steinbeck
Rok vydání: 1998
Předmět:
Adult
Male
medicine.medical_specialty
ERG1 Potassium Channel
Potassium Channels
Heart disease
Transcription
Genetic

medicine.medical_treatment
Heart Ventricles
Action Potentials
Muscle Proteins
Downregulation and upregulation
Transcriptional Regulator ERG
Physiology (medical)
Internal medicine
medicine
Repolarization
Humans
RNA
Messenger

Cation Transport Proteins
Cells
Cultured

Aged
Heart transplantation
Heart Failure
Cardiac transient outward potassium current
Ion Transport
business.industry
Myocardium
Middle Aged
medicine.disease
Potassium channel
Ether-A-Go-Go Potassium Channels
DNA-Binding Proteins
Electrophysiology
Endocrinology
Death
Sudden
Cardiac

Shal Potassium Channels
Potassium Channels
Voltage-Gated

Heart failure
Potassium
Trans-Activators
Heart Transplantation
Female
Calcium Channels
Cardiology and Cardiovascular Medicine
business
Zdroj: Circulation. 98(14)
ISSN: 0009-7322
Popis: 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 Ca 2+ -independent transient outward current ( I to ). The mechanism for the reduction of I to in heart failure is unknown. The K + channel α-subunit Kv4.3, a homolog of the Drosophila Shal family, is most likely to encode all or part of the native cardiac I to in humans. Methods and Results —We used ribonuclease protection assays and whole-cell electrophysiological recording to study changes in the level of Kv4.3 mRNA and I to 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 I to 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, Kvβ1.3, and the α1C subunit of the Ca 2+ 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 I to in humans and that part of the downregulation of this current in heart failure may be transcriptionally regulated.
Databáze: OpenAIRE