Kcne4 deletion sex- and age-specifically impairs cardiac repolarization in mice
| Autor: | Zhaoyang Hu, Geoffrey W. Abbott, Ritu Kant, Steve A.N. Goldstein, Daniel I. Levy, Shawn M. Crump |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Heart Ventricles Action Potentials CHO Cells Biochemistry Membrane Potentials 03 medical and health sciences Research Communication Mice Cricetulus Sex Factors Internal medicine Cricetinae Genetics medicine Myocyte Animals Myocytes Cardiac Testosterone Orchiectomy Molecular Biology Cells Cultured biology Age Factors Atrial fibrillation KCNE4 medicine.disease Potassium channel Cardiovascular physiology Mice Inbred C57BL 030104 developmental biology Endocrinology medicine.anatomical_structure Ventricle Potassium Channels Voltage-Gated biology.protein Female Gene Deletion Biotechnology |
| Popis: | Myocardial repolarization capacity varies with sex, age, and pathology; the molecular basis for this variation is incompletely understood. Here, we show that the transcript for KCNE4, a voltage-gated potassium (Kv) channel β subunit associated with human atrial fibrillation, was 8-fold more highly expressed in the male left ventricle compared with females in young adult C57BL/6 mice (P < 0.05). Similarly, Kv current density was 25% greater in ventricular myocytes from young adult males (P < 0.05). Germ-line Kcne4 deletion eliminated the sex-specific Kv current disparity by diminishing ventricular fast transient outward current (Ito,f) and slowly activating K+ current (IK,slow1). Kcne4 deletion also reduced Kv currents in male mouse atrial myocytes, by >45% (P < 0.001). As we previously found for Kv4.2 (which generates mouse Ito,f), heterologously expressed KCNE4 functionally regulated Kv1.5 (the Kv α subunit that generates IKslow1 in mice). Of note, in postmenopausal female mice, ventricular repolarization was impaired by Kcne4 deletion, and ventricular Kcne4 expression increased to match that of males. Moreover, castration diminished male ventricular Kcne4 expression 2.8-fold, whereas 5α-dihydrotestosterone (DHT) implants in castrated mice increased Kcne4 expression >3-fold (P = 0.01) to match noncastrated levels. KCNE4 is thereby shown to be a DHT-regulated determinant of cardiac excitability and a molecular substrate for sex- and age-dependent cardiac arrhythmogenesis.—Crump, S. M., Hu, Z., Kant, R., Levy, D. I., Goldstein, S. A. N., Abbott, G. W. Kcne4 deletion sex- and age-specifically impairs cardiac repolarization in mice. |
| Databáze: | OpenAIRE |
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