title: Acute slowing of cardiac conduction in response to myofibroblast coupling to cardiomyocytes through N-cadherin.
abstract: The electrophysiological consequences of cardiomyocyte and myofibroblast interactions remain unclear, and the contribution of mechanical coupling between these two cell types is still poorly understood. In this study, we examined the time course and mechanisms by which addition of myofibroblasts activated by transforming growth factor-beta (TGF-β) influence the conduction velocity (CV) of neonatal rat ventricular cell monolayers. We observed that myofibroblasts affected CV within 30 min of contact and that these effects were temporally correlated with membrane deformation of cardiomyocytes by the myofibroblasts. Expression of dominant negative RhoA in the myofibroblasts impaired both myofibroblast contraction and myofibroblast-induced slowing of cardiac conduction, whereas overexpression of constitutive RhoA had little effect. To determine the importance of mechanical coupling between these cell types, we examined the expression of the two primary cadherins in the heart (N- and OB-cadherin) at cell-cell contacts formed between myofibroblasts and cardiomyocytes. Although OB-cadherin was frequently found at myofibroblast-myofibroblast contacts, very little expression was observed at myofibroblast-cardiomyocyte contacts. The myofibroblast-induced slowing of cardiac conduction was not prevented by silencing of OB-cadherin in the myofibroblasts, and could be reversed by inhibitors of mechanosensitive channels (gadolinium or streptomycin) and cellular contraction (blebbistatin). In contrast, N-cadherin expression was commonly observed at myofibroblast-cardiomyocyte contacts, and silencing of N-cadherin in myofibroblasts prevented the myofibroblast-dependent slowing of cardiac conduction. We propose that myofibroblasts can impair the electrophysiological function of cardiac tissue through the application of contractile force to the cardiomyocyte membrane via N-cadherin junctions.
authors.affiliation: Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Thompson
authors.affiliation: Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Adriana
authors.initials: A
authors.lastname: Blazeski
authors.affiliation: Department of Physics and Astronomy, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Craig R
authors.initials: CR
authors.lastname: Copeland
authors.affiliation: Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Cohen
authors.affiliation: Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Chen
authors.affiliation: Department of Physics and Astronomy, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Reich
authors.affiliation: Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, MD, USA. Electronic address: ltung@jhu.edu.
authors.forename: Leslie
authors.initials: L
authors.lastname: Tung
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D002465:Cell Movement; D002478:Cells, Cultured; D018920:Coculture Techniques; D056966:Excitation Contraction Coupling; D006329:Heart Conduction System / Q000378:metabolism / Q000503:physiopathology*; D020125:Mutation, Missense; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism*; D058628:Myofibroblasts / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D051381:Rats; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D015820:Cadherins; C570099:N-cadherin, rat; D009419:Nerve Tissue Proteins; D020742:rhoA GTP-Binding Protein
keywords: Cadherin; Cardiomyocyte; Electrophysiology; Mechanobiology; Myofibroblast; Optical mapping