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Inhibition of platelet-derived growth factor-AB signaling prevents electromechanical remodeling of adult atrial myocytes that contact myofibroblasts.

AbstractBACKGROUND:
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.
AuthorsHassan Musa, Kuljeet Kaur, Ryan O'Connell, Matt Klos, Guadalupe Guerrero-Serna, Uma Mahesh R Avula, Todd J Herron, Jerômé Kalifa, Justus M B Anumonwo, José Jalife
JournalHeart rhythm : the official journal of the Heart Rhythm Society (Heart Rhythm) Vol. 10 Issue 7 Pg. 1044-51 (Jul 2013) ISSN: 1556-3871 [Electronic] United States
PMID23499624 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)
CopyrightCopyright © 2013 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.
Chemical References
  • Platelet-Derived Growth Factor
  • platelet-derived growth factor AB
Topics
  • Action Potentials (drug effects)
  • Animals
  • Atrial Fibrillation (drug therapy, metabolism, physiopathology)
  • Cells, Cultured
  • Disease Models, Animal
  • Electrophysiologic Techniques, Cardiac
  • Heart Atria (metabolism, pathology, physiopathology)
  • Myocytes, Cardiac (drug effects, metabolism, pathology)
  • Platelet-Derived Growth Factor (antagonists & inhibitors, metabolism)
  • Sheep
  • Signal Transduction (drug effects)

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