TY - JOUR
T1 - Ablation of androgen receptor gene triggers right ventricular outflow tract ventricular tachycardia
AU - Tsai, Wen Chin
AU - Lu, Yen Yu
AU - Chen, Yao Chang
AU - Chang, Chien Jung
AU - Kao, Yu Hsun
AU - Lin, Yung Kuo
AU - Chen, Yu Hsin
AU - Chen, Shih Ann
AU - Yang, Liang Yo
AU - Chen, Yi Jen
N1 - Publisher Copyright:
© 2015 Elsevier Ireland Ltd. All rights reserved.
PY - 2015/8/1
Y1 - 2015/8/1
N2 - Background: Sex hormones and calcium (Ca2+) regulation play roles in the pathophysiology of ventricular tachycardia from right ventricular outflow tract (RVOT). The purpose of this study was to evaluate whether androgen receptor knockout (ARKO) can increase RVOT arrhythmogenesis through modulating RVOT electrophysiology and Ca2+ homeostasis. Methods: Conventional microelectrodes were used to study the action potential (AP) in RVOT tissues prepared from wild type (WT) and ARKO mice (aged 6-10 months) before and after caffeine (1 mM), isoproterenol (1 μM), adenosine (10 μM) and flecainide (5 μM) administration. The Fluo-3 fluorescence Ca2+ imaging with confocal microscopy and western blots were used to investigate intracellular Ca2+ (Ca2+i) transients, Ca2+ sparks, and the expressions of ionic channel proteins in ARKO and WT RVOT myocytes. Results: We found that ARKO RVOTs (n = 13) had longer AP duration, faster burst firing (5.4 ± 0.7 vs. 3.4 ± 0.7 Hz, P <0.05), and higher incidence of early afterdepolarizations (82% vs. 8%, P <0.001) than WT RVOTs (n = 11). Adenosine and flecainide can suppress caffeine- or isoproterenol-induced spontaneous rates and burst firing in WT RVOTs, but not in ARKO RVOTs. ARKO RVOT myocytes had a higher frequency (7.7 ± 2.8 vs. 1.3 ± 0.4 spark/mm/s, P <0.05) and incidence (89% vs. 47%, P <0.05) of Ca2+ sparks, and greater expressions of Cav1.2, NCX, phosphorylated RyR (s2814), phosphorylated phospholamban (Thr17), CAMKII and GRK2 than WT RVOT myocytes. However, ARKO and WT RVOT myocytes exhibit similar Ca2+i transients and SR Ca2+ content, and less expression of calsequestrin. Conclusions: ARKO changes RVOT electrophysiology and Ca2+ homeostasis with increased ventricular arrhythmogenesis.
AB - Background: Sex hormones and calcium (Ca2+) regulation play roles in the pathophysiology of ventricular tachycardia from right ventricular outflow tract (RVOT). The purpose of this study was to evaluate whether androgen receptor knockout (ARKO) can increase RVOT arrhythmogenesis through modulating RVOT electrophysiology and Ca2+ homeostasis. Methods: Conventional microelectrodes were used to study the action potential (AP) in RVOT tissues prepared from wild type (WT) and ARKO mice (aged 6-10 months) before and after caffeine (1 mM), isoproterenol (1 μM), adenosine (10 μM) and flecainide (5 μM) administration. The Fluo-3 fluorescence Ca2+ imaging with confocal microscopy and western blots were used to investigate intracellular Ca2+ (Ca2+i) transients, Ca2+ sparks, and the expressions of ionic channel proteins in ARKO and WT RVOT myocytes. Results: We found that ARKO RVOTs (n = 13) had longer AP duration, faster burst firing (5.4 ± 0.7 vs. 3.4 ± 0.7 Hz, P <0.05), and higher incidence of early afterdepolarizations (82% vs. 8%, P <0.001) than WT RVOTs (n = 11). Adenosine and flecainide can suppress caffeine- or isoproterenol-induced spontaneous rates and burst firing in WT RVOTs, but not in ARKO RVOTs. ARKO RVOT myocytes had a higher frequency (7.7 ± 2.8 vs. 1.3 ± 0.4 spark/mm/s, P <0.05) and incidence (89% vs. 47%, P <0.05) of Ca2+ sparks, and greater expressions of Cav1.2, NCX, phosphorylated RyR (s2814), phosphorylated phospholamban (Thr17), CAMKII and GRK2 than WT RVOT myocytes. However, ARKO and WT RVOT myocytes exhibit similar Ca2+i transients and SR Ca2+ content, and less expression of calsequestrin. Conclusions: ARKO changes RVOT electrophysiology and Ca2+ homeostasis with increased ventricular arrhythmogenesis.
KW - Arrhythmogenicity
KW - Calcium handling
KW - Right ventricular outflow tract
KW - Ventricular arrhythmias
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U2 - 10.1016/j.ijcard.2015.04.080
DO - 10.1016/j.ijcard.2015.04.080
M3 - Article
C2 - 25897899
AN - SCOPUS:84929466098
SN - 0167-5273
VL - 189
SP - 172
EP - 181
JO - International Journal of Cardiology
JF - International Journal of Cardiology
IS - 1
ER -