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 |
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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 |
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