Atrial fibrillation and electrophysiology in transgenic mice with cardiac-restricted overexpression of FKBP12

Zhenwei Pan, Tomohiko Ai, Po Cheng Chang, Ying Liu, Jijia Liu, Mitsunori Maruyama, Mohamed Homsi, Michael C. Fishbein, Michael Rubart, Shien Fong Lin, Deyong Xiao, Hanying Chen, Peng Sheng Chen, Weinian Shou, Bai Yan Li

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Cardiomyocyte-restricted overexpression of FK506-binding protein 12 transgenic (αMyHC-FKBP12) mice develop spontaneous atrial fibrillation (AF). The aim of the present study is to explore the mechanisms underlying the occurrence of AF in αMyHC-FKBP12 mice. Spontaneous AF was documented by telemetry in vivo and Langendorff-perfused hearts of αMyHC-FKBP12 and littermate control mice in vitro. Atrial conduction velocity was evaluated by optical mapping. The patch-clamp technique was applied to determine the potentially altered electrophysiology in atrial myocytes. Channel protein expression levels were evaluated by Western blot analyses. Spontaneous AF was recorded in four of seven αMyHC-FKBP12 mice but in none of eight nontransgenic (NTG) controls. Atrial conduction velocity was significantly reduced in αMyHC-FKBP12 hearts compared with NTG hearts. Interestingly, the mean action potential duration at 50% but not 90% was significantly prolonged in αMyHC-FKBP12 atrial myocytes compared with their NTG counterparts. Consistent with decreased conduction velocity, average peak Na+ current (INa) density was dramatically reduced and the INa inactivation curve was shifted by approximately +7 mV in αMyHC-FKBP12 atrial myocytes, whereas the activation and recovery curves were unaltered. The Nav1.5 expression level was significantly reduced in αMyHC-FKBP12 atria. Furthermore, we found increases in atrial Cav1.2 protein levels and peak L-type Ca2+ current density and increased levels of fibrosis in αMyHC-FKBP12 atria. In summary, cardiomyocyte-restricted overexpression of FKBP12 reduces the atrial Nav1.5 expression level and mean peak INa, which is associated with increased peak L-type Ca2+ current and interstitial fibrosis in atria. The combined electrophysiological and structural changes facilitated the development of local conduction block and altered action potential duration and spontaneous AF. NEW & NOTEWORTHY This study addresses a long-standing riddle regarding the role of FK506-binding protein 12 in cardiac physiology. The work provides further evidence that FK506-binding protein 12 is a critical component for regulating voltage-gated sodium current and in so doing has an important role in arrhythmogenic physiology, such as atrial fibrillation.

Original languageEnglish
Pages (from-to)H371-H379
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume316
Issue number2
DOIs
StatePublished - Feb 2019

Keywords

  • Action potential duration
  • Cardiac electrophysiology
  • Fibrosis
  • Ion channels
  • Patch clamp
  • Voltage-gated sodium current

Fingerprint Dive into the research topics of 'Atrial fibrillation and electrophysiology in transgenic mice with cardiac-restricted overexpression of FKBP12'. Together they form a unique fingerprint.

Cite this