title: Ablation of the androgen receptor gene modulates atrial electrophysiology and arrhythmogenesis with calcium protein dysregulation.
abstract: Androgen deficiency is important in the pathophysiology of atrial fibrillation. Androgen regulates cardiac electrophysiology and calcium (Ca(2+)) homeostasis. The purpose of this study is to evaluate whether androgen receptor knockout (ARKO) can modulate atrial electrophysiology and arrhythmogenesis with modulation of Ca(2+) homeostasis proteins. We used conventional microelectrodes to study the action potential (AP) in left atrium (LA) tissues prepared from wild-type (WT) and ARKO mice (aged 6-10 months) before and after the administration of isoproterenol, hypocalcemic/hypercalcemic solutions, and ouabain. Echocardiography and Western blots were used to evaluate the cardiac function and expression levels of ionic channel proteins in WT and ARKO LAs. ARKO LAs had larger LA diameter with decreased LA fractional shortening than did WT LAs. In the current study, we found that ARKO LAs had a lower negative resting membrane potential and a greater 90% AP duration (APD) than did WT LAs. Isoproterenol increased the incidence and amplitude of delayed afterdepolarizations (DADs) in ARKO LAs but not in WT LAs. Hypocalcemic solutions prolonged APD in WT and ARKO LAs but increased DAD amplitude only in ARKO LAs. Hypercalcemic solutions shortened APD in ARKO LAs but not in WT LAs. Ouabain increased DAD amplitude in ARKO LAs but not in WT LAs. ARKO LAs expressed higher amounts of Ca(2+)/calmodulin-dependent protein kinase II, Na(+)/Ca(2+) exchanger, and phosphorylated phospholamban (Ser-16/Thr-17 site) and less Cav1.2, Kir2.1, Kir3.1, and Kv7.1 than WT LAs. These observations indicate that ARKO alters atrial electrophysiology with increased atrial arrhythmogenesis.
authors.affiliation: Division of Cardiology, Tzu-Chi General Hospital, Hualien 970, Taiwan.
authors.forename: Wen-Chin
authors.initials: WC
authors.lastname: Tsai
authors.forename: Liang-Yo
authors.initials: LY
authors.lastname: Yang
authors.forename: Yao-Chang
authors.initials: YC
authors.lastname: Chen
authors.forename: Yu-Hsun
authors.initials: YH
authors.lastname: Kao
authors.forename: Yung-Kuo
authors.initials: YK
authors.lastname: Lin
authors.forename: Shih-Ann
authors.initials: SA
authors.lastname: Chen
authors.forename: Ching-Feng
authors.initials: CF
authors.lastname: Cheng
authors.forename: Yi-Jen
authors.initials: YJ
authors.lastname: Chen
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000503:physiopathology*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology; D004452:Echocardiography; D055724:Electrophysiological Phenomena; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006325:Heart Atria / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D051665:Kv1.4 Potassium Channel / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010042:Ouabain / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D011944:Receptors, Androgen / Q000172:deficiency* / Q000235:genetics; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D000099211:Phospholamban
chemical_list: D002118:Calcium; D020746:Calcium Channels, L-Type; D002135:Calcium-Binding Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002316:Cardiotonic Agents; D007545:Isoproterenol; D051665:Kv1.4 Potassium Channel; D010042:Ouabain; D024661:Potassium Channels, Inwardly Rectifying; D011944:Receptors, Androgen; D019831:Sodium-Calcium Exchanger; D000099211:Phospholamban; C489461:Kir2.1 channel; C419385:L-type calcium channel alpha(1C)