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Kcne4 deletion sex‐ and age‐specifically impairs cardiac repolarization in mice
Author(s) -
Crump Shawn M.,
Hu Zhaoyang,
Kant Ritu,
Levy Daniel I.,
Goldstein Steve A. N.,
Abbott Geoffrey W.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.15-278754
Subject(s) - medicine , endocrinology , cardiac transient outward potassium current , ventricle , potassium channel , repolarization , myocyte , biology , chemistry , electrophysiology , patch clamp
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 (K v )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, K v current density was 25% greater in ventricular myocytes from young adult males ( P < 0.05). Germ‐line Kcne4 deletion eliminated the sex‐specific K v current disparity by diminishing ventricular fast transient outward current ( I to,f ) and slowly activating K + current ( I K,slow1 ). Kcne4 deletion also reduced K v currents in male mouse atrial myocytes, by >45% ( P < 0.001). As we previously found for K v 4.2 (which generates mouse I to,f ), heterologously expressed KCNE4 functionally regulated K v 1.5 (the K v α subunit that generates I Kslow1 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 5a‐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. FASEB J. 30, 360‐369 (2016). www.fasebj.org