LKB1 deletion causes early changes in atrial channel expression and electrophysiology prior to atrial fibrillation

Grace E. Kim, Jenna L. Ross, Chaoqin Xie, Kevin N. Su, Vlad G. Zaha, Xiaohong Wu, Monica Palmeri, Mohammed Ashraf, Joseph G. Akar, Kerry S. Russell, Fadi G. Akar, Lawrence H. Young

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Aims Liver kinase B1 (LKB1) is a protein kinase that activates the metabolic regulator AMP-activated protein kinase (AMPK) and other related kinases. Deletion of LKB1 in mice leads to cardiomyopathy and atrial fibrillation (AF). However, the specific role of the LKB1 pathway in early atrial biology remains unknown. Thus, we investigated whether LKB1 deletion altered atrial channel expression and electrophysiological function in a cardiomyocyte-specific knockout mouse model. Methods and results We performed a systematic comparison of αMHC-Cre LKB1fl/fl and littermate LKB1fl/fl male mice. This included analysis of gene expression, histology, and echocardiography, as well as cellular and tissue-level electrophysiology using patch-clamp recordings in vitro, optical mapping ex vivo, and ECG recordings in vivo. At postnatal day 1, atrial depolarization was prolonged, and Nav1.5 and Cx40 expression were markedly down-regulated in MHC-Cre LKB1fl/fl mice. Inward sodium current density was significantly decreased in MHC-Cre LKB1fl/fl neonatal atrial myocytes. Subsequently, additional alterations in atrial channel expression, atrial fibrosis, and spontaneous onset of AF developed by 2 weeks of age. In adult mice, abnormalities of interatrial conduction and bi-atrial electrical coupling were observed, likely promoting the perpetuation of AF. Mice with AMPK-inactivated hearts demonstrated modest overlap in channel expression with MHC-Cre LKB1fl/fl hearts, but retained normal structure, electrophysiological function and contractility. Conclusions Deletion of LKB1 causes early defects in atrial channel expression, action potential generation and conduction, which precede widespread atrial remodelling, fibrosis and AF. LKB1 is critical for normal atrial growth and electrophysiological function.

Original languageEnglish (US)
Pages (from-to)197-208
Number of pages12
JournalCardiovascular Research
Volume108
Issue number1
DOIs
StatePublished - May 21 2015

Keywords

  • Atrial fibrillation
  • Cellular signalling pathways
  • LKB1

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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