Ablation of androgen receptor gene triggers right ventricular outflow tract ventricular tachycardia

Wen Chin Tsai, Yen Yu Lu, Yao Chang Chen, Chien Jung Chang, Yu Hsun Kao, Yung Kuo Lin, Yu Hsin Chen, Shih Ann Chen, Liang Yo Yang, Yi Jen Chen

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)172-181
Number of pages10
JournalInternational Journal of Cardiology
Volume189
Issue number1
DOIs
Publication statusPublished - Aug 1 2015

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Keywords

  • Arrhythmogenicity
  • Calcium handling
  • Right ventricular outflow tract
  • Ventricular arrhythmias

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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