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 arrhythmogenesiswithmodulationofCa2 +homeostasisproteins.Weusedconventional microelectrodes to study the action potential (AP) in left atrium (LA) tissues prepared from wild-type (WT)andARKOmice (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 inWTandARKOLAs.ARKOLAs 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 inWTLAs. Ouabain increasedDADamplitude inARKOLAs but not inWTLAs.ARKOLAs expressed higher amounts of Ca2+/calmodulin-dependent protein kinase II, Na+/Ca 2+ exchanger, and phosphorylatedphospholamban( Ser-16/Thr-17 site)andless Cav1.2, Kir2.1, Kir3.1,andKv7.1 thanWTLAs. These observationsindicatethatARKOalters atrialelectrophysiologywithincreasedatrialarrhythmogenesis. © 2013 by The Endocrine Society.