title: Inhibition of platelet-derived growth factor-AB signaling prevents electromechanical remodeling of adult atrial myocytes that contact myofibroblasts.
abstract: BACKGROUND
  Persistent atrial fibrillation (PAF) results in electromechanical and structural remodeling by mechanisms that are poorly understood. Myofibroblast proliferation and fibrosis are major sources of structural remodeling in PAF. Myofibroblasts also interact with atrial myocytes via direct physical contact and release of signaling molecules, which may contribute to remodeling.
  
  
  OBJECTIVE
  To determine whether myofibroblasts contribute to atrial myocyte electromechanical remodeling via direct physical contact and platelet-derived growth factor (PDGF) signaling.
  
  
  METHODS
  Myofibroblasts and myocytes from adult sheep atria were co-cultured for 24 hours. Alternatively adult sheep atrial myocytes were exposed to 1 ng/mL recombitant PDGF AB peptide for 24 hours.
  
  
  RESULTS
  Myocytes making contact with myofibroblasts demonstrated significant reduction (P ≤ .05) in peak L-type calcium current density, shortening of action potential duration (APD), and reduction in calcium transients. These effects were blocked by pretreatment with a PDGF-AB neutralizing anti-body. Heterocellular contact also severely disturbed the localization of the L-type calcium channel. Myocytes exposed to recombinant PDGF-AB peptide for 24 hours demonstrated reduced APD50, APD80 and Peak L-type calcium current. Pretreatment with a PDGF-AB neutralizing antibody prevented these effects. Finally, while control atrial myocytes did not respond in a 1:1 manner to pacing frequencies of 3 Hz or higher, atrial myocytes from hearts that were tachypaced for 2 months and normal myocytes treated with PDGF-AB for 24 hours could be paced up to 10 Hz.
  
  
  CONCLUSIONS
  In addition to leading to fibrosis, atrial myofibroblasts contribute to electromechanical remodeling of myocytes via direct physical contact and release of PDGF-AB, which may be a factor in PAF-induced remodeling.
authors.affiliation: Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan 48109, USA. hasanmus@umich.edu
authors.forename: Hassan
authors.initials: H
authors.lastname: Musa
authors.forename: Kuljeet
authors.initials: K
authors.lastname: Kaur
authors.forename: Ryan
authors.initials: R
authors.lastname: O'Connell
authors.forename: Matt
authors.initials: M
authors.lastname: Klos
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Guerrero-Serna
authors.forename: Uma Mahesh R
authors.initials: UM
authors.lastname: Avula
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Herron
authors.forename: Jerômé
authors.initials: J
authors.lastname: Kalifa
authors.forename: Justus M B
authors.initials: JM
authors.lastname: Anumonwo
authors.forename: José
authors.initials: J
authors.lastname: Jalife
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D022062:Electrophysiologic Techniques, Cardiac; D006325:Heart Atria / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012756:Sheep; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D010982:Platelet-Derived Growth Factor; C095477:platelet-derived growth factor AB