title: Atrial Fibrillation Activates AMP-Dependent Protein Kinase and its Regulation of Cellular Calcium Handling: Potential Role in Metabolic Adaptation and Prevention of Progression.
abstract: BACKGROUND
  Atrial fibrillation (AF) is associated with metabolic stress, which activates adenosine monophosphate-regulated protein kinase (AMPK).
  
  
  OBJECTIVE
  This study sought to examine AMPK response to AF and associated metabolic stress, along with consequences for atrial cardiomyocyte Ca(2+) handling.
  
  
  METHODS
  Calcium ion (Ca(2+)) transients (CaTs) and cell shortening (CS) were measured in dog and human atrial cardiomyocytes. AMPK phosphorylation and AMPK association with Ca(2+)-handling proteins were evaluated by immunoblotting and immunoprecipitation.
  
  
  RESULTS
  CaT amplitude and CS decreased at 4-min glycolysis inhibition (GI) but returned to baseline at 8 min, suggesting cellular adaptation to metabolic stress, potentially due to AMPK activation. GI increased AMPK-activating phosphorylation, and an AMPK inhibitor, compound C (CompC), abolished the adaptation of CaT and CS to GI. The AMPK activator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) increased CaT amplitude and CS, restoring CompC-induced CaT and CS decreases. CompC decreased L-type calcium channel current (ICa,L), along with ICa,L-triggered CaT amplitude and sarcoplasmic reticulum (SR) Ca(2+) content under voltage clamp conditions in dog cells and suppressed CaT and ICa,L in human cardiomyocytes. Small interfering ribonucleic acid-based AMPK knockdown decreased CaT amplitude in neonatal rat cardiomyocytes. L-type Ca(2+) channel α subunits coimmunoprecipitated with AMPKα. Atrial AMPK-activating phosphorylation was enhanced by 1 week of electrically maintained AF in dogs; fractional AMPK phosphorylation was increased in paroxysmal AF and reduced in longstanding persistent AF patients.
  
  
  CONCLUSIONS
  AMPK is activated by metabolic stress and AF, and helps maintain the intactness of atrial ICa,L, Ca(2+) handling, and cell contractility. AMPK contributes to the atrial compensatory response to AF-related metabolic stress; AF-related metabolic responses may be an interesting new therapeutic target.
authors.affiliation: Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada; Department of Cardiology, Fujita Health University School of Medicine, Toyoake, Japan.
authors.forename: Masahide
authors.initials: M
authors.lastname: Harada
authors.affiliation: Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Artavazd
authors.initials: A
authors.lastname: Tadevosyan
authors.affiliation: Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Qi
authors.affiliation: Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Jiening
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.affiliation: Institute of Pharmacology, West German Cardiac and Vascular Center, School of Medicine, University Duisburg-Essen, Essen, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Voigt
authors.affiliation: Department of Cardiac Surgery, Heidelberg University, Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Karck
authors.affiliation: Department of Cardiac Surgery, Huttrop Heart Center, Essen, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Kamler
authors.affiliation: Nagoya University, Nagoya, Japan.
authors.forename: Itsuo
authors.initials: I
authors.lastname: Kodama
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
authors.affiliation: Institute of Pharmacology, West German Cardiac and Vascular Center, School of Medicine, University Duisburg-Essen, Essen, Germany.
authors.forename: Dobromir
authors.initials: D
authors.lastname: Dobrev
authors.affiliation: Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada. Electronic address: stanley.nattel@icm-mhi.org.
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001281:Atrial Fibrillation / Q000201:enzymology*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004285:Dogs; D004789:Enzyme Activation; D006801:Humans; D032383:Myocytes, Cardiac / Q000201:enzymology*; D051381:Rats; D013312:Stress, Physiological
chemical_list: D055372:AMP-Activated Protein Kinases; D002118:Calcium
keywords: cell calcium handling; heart pharmacology; myocardial energy metabolism