title: Abolishing myofibroblast arrhythmogeneicity by pharmacological ablation of α-smooth muscle actin containing stress fibers.
abstract: BACKGROUND
  Myofibroblasts typically appear in the myocardium after insults to the heart like mechanical overload and infarction. Apart from contributing to fibrotic remodeling, myofibroblasts induce arrhythmogenic slow conduction and ectopic activity in cardiomyocytes after establishment of heterocellular electrotonic coupling in vitro. So far, it is not known whether α-smooth muscle actin (α-SMA) containing stress fibers, the cytoskeletal components that set myofibroblasts apart from resident fibroblasts, are essential for myofibroblasts to develop arrhythmogenic interactions with cardiomyocytes.
  
  
  OBJECTIVE
  We investigated whether pharmacological ablation of α-SMA containing stress fibers by actin-targeting drugs affects arrhythmogenic myofibroblast-cardiomyocyte cross-talk.
  
  
  RESULTS
  Experiments were performed with patterned growth cell cultures of neonatal rat ventricular cardiomyocytes coated with cardiac myofibroblasts. The preparations exhibited slow conduction and ectopic activity under control conditions. Exposure to actin-targeting drugs (Cytochalasin D, Latrunculin B, Jasplakinolide) for 24 hours led to disruption of α-SMA containing stress fibers. In parallel, conduction velocities increased dose-dependently to values indistinguishable from cardiomyocyte-only preparations and ectopic activity measured continuously over 24 hours was completely suppressed. Mechanistically, antiarrhythmic effects were due to myofibroblast hyperpolarization (Cytochalasin D, Latrunculin B) and disruption of heterocellular gap junctional coupling (Jasplakinolide), which caused normalization of membrane polarization of adjacent cardiomyocytes.
  
  
  CONCLUSIONS
  The results suggest that α-SMA containing stress fibers importantly contribute to myofibroblast arrhythmogeneicity. After ablation of this cytoskeletal component, cells lose their arrhythmic effects on cardiomyocytes, even if heterocellular electrotonic coupling is sustained. The findings identify α-SMA containing stress fibers as a potential future target of antiarrhythmic therapy in hearts undergoing structural remodeling.
authors.affiliation: Dept. of Physiology, University of Bern, Bühlplatz 5, CH-3012 Bern, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Rosker
authors.forename: Nicolò
authors.initials: N
authors.lastname: Salvarani
authors.forename: Stephan
authors.initials: S
authors.lastname: Schmutz
authors.forename: Teddy
authors.initials: T
authors.lastname: Grand
authors.forename: Stephan
authors.initials: S
authors.lastname: Rohr
mesh_terms: D000199:Actins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000200:Action Potentials; D000818:Animals; D000831:Animals, Newborn; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002450:Cell Communication / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D015638:Cytochalasin D / Q000494:pharmacology; D047630:Depsipeptides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D058628:Myofibroblasts / Q000187:drug effects* / Q000378:metabolism; D010641:Phenotype; D051381:Rats; D017208:Rats, Wistar; D022502:Stress Fibers / Q000187:drug effects* / Q000378:metabolism; D053778:Thiazolidines / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000199:Actins; D000889:Anti-Arrhythmia Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D015638:Cytochalasin D; D047630:Depsipeptides; D053778:Thiazolidines; C498862:Acta2 protein, rat; C057531:jasplakinolide; C037068:latrunculin B