Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Rosker, C; Salvarani, N; Schmutz, S; Grand, T; Rohr, S.
Abolishing myofibroblast arrhythmogeneicity by pharmacological ablation of á-smooth muscle actin containing stress fibers.
Circ Res. 2011; 109(10):1120-1131
Doi: 10.1161/CIRCRESAHA.111.244798
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- Führende Autor*innen der Med Uni Graz
- Rosker Christian
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- Abstract:
- RATIONALE: 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 á-smooth muscle actin (á-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 á-SMA containing stress fibers by actin-targeting drugs affects arrhythmogenic myofibroblast-cardiomyocyte cross-talk. METHODS AND 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 á-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 á-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 á-SMA containing stress fibers as a potential future target of antiarrhythmic therapy in hearts undergoing structural remodeling.
- Find related publications in this database (using NLM MeSH Indexing)
- Actins - antagonists and inhibitors Actins - metabolism
- Action Potentials -
- Animals -
- Animals, Newborn -
- Anti-Arrhythmia Agents - pharmacology
- Arrhythmias, Cardiac - drug therapy Arrhythmias, Cardiac - metabolism
- Bicyclo Compounds, Heterocyclic - pharmacology
- Cell Communication - drug effects
- Cell Shape - drug effects
- Cells, Cultured -
- Coculture Techniques -
- Cytochalasin D - pharmacology
- Depsipeptides - pharmacology
- Dose-Response Relationship, Drug -
- Gap Junctions - drug effects Gap Junctions - metabolism
- Myocytes, Cardiac - drug effects Myocytes, Cardiac - metabolism
- Myofibroblasts - drug effects Myofibroblasts - metabolism
- Phenotype -
- Rats -
- Rats, Wistar -
- Stress Fibers - drug effects Stress Fibers - metabolism
- Thiazolidines - pharmacology
- Time Factors -
- Find related publications in this database (Keywords)
- arrhythmia
- conduction
- fibroblast
- gap junction
- myocardial structure