Background - TGF-β1(transforming growth factor-β1) importantly contributes to cardiac fibrosis by controlling differentiation, migration, and collagen secretion of cardiac myofibroblasts. It is still elusive, however, to which extent TGF-β1alters the electrophysiological phenotype of myofibroblasts and cardiomyocytes and whether it affects proarrhythmic myofibroblast-cardiomyocyte crosstalk observed in vitro. Methods and Results - Patch-clamp recordings of cultured neonatal rat ventricular myofibroblasts revealed that TGF-β1, applied for 24 to 48 hours at clinically relevant concentrations (≤2.5 ng/mL), causes substantial membrane depolarization concomitant with a several-fold increase of transmembrane currents. Transcriptome analysis revealed TGF-β1-dependent changes in 29 of 63 ion channel/pump/connexin transcripts, indicating a pleiotropic effect on the electrical phenotype of myofibroblasts. Whereas not affecting cardiomyocyte membrane potentials and cardiomyocyte-cardiomyocyte gap junctional coupling, TGF-β1depolarized cardiomyocytes coupled to myofibroblasts by ≈20 mV and increased gap junctional coupling between myofibroblasts and cardiomyocytes >5-fold as reflected by elevated connexin 43 and consortin transcripts. TGF-β1-dependent cardiomyocyte depolarization resulted from electrotonic crosstalk with myofibroblasts as demonstrated by immediate normalization of cardiomyocyte electrophysiology after targeted disruption of coupled myofibroblasts and by cessation of ectopic activity of cardiomyocytes coupled to myofibroblasts during pharmacological gap junctional uncoupling. In cardiac fibrosis models exhibiting slow conduction and ectopic activity, block of TGF-β1signaling completely abolished both arrhythmogenic conditions. Conclusions - TGF-β1profoundly alters the electrophysiological phenotype of cardiac myofibroblasts. Apart from possibly contributing to the control of cell function in general, the changes proved to be pivotal for proarrhythmic myofibroblast-cardiomyocyte crosstalk in vitro, which suggests that TGF-β1may play a potentially important role in arrhythmogenesis of the fibrotic heart.

TGF-β1(Transforming Growth Factor-β1) Plays a Pivotal Role in Cardiac Myofibroblast Arrhythmogenicity / Salvarani, Nicolã²; Maguy, Ange; De Simone, Stefano A.; Miragoli, Michele; Jousset, Florian; Rohr, Stephan. - In: CIRCULATION. ARRHYTHMIA AND ELECTROPHYSIOLOGY. - ISSN 1941-3149. - 10:5(2017), p. e004567. [10.1161/CIRCEP.116.004567]

TGF-β1(Transforming Growth Factor-β1) Plays a Pivotal Role in Cardiac Myofibroblast Arrhythmogenicity

Miragoli, Michele;
2017

Abstract

Background - TGF-β1(transforming growth factor-β1) importantly contributes to cardiac fibrosis by controlling differentiation, migration, and collagen secretion of cardiac myofibroblasts. It is still elusive, however, to which extent TGF-β1alters the electrophysiological phenotype of myofibroblasts and cardiomyocytes and whether it affects proarrhythmic myofibroblast-cardiomyocyte crosstalk observed in vitro. Methods and Results - Patch-clamp recordings of cultured neonatal rat ventricular myofibroblasts revealed that TGF-β1, applied for 24 to 48 hours at clinically relevant concentrations (≤2.5 ng/mL), causes substantial membrane depolarization concomitant with a several-fold increase of transmembrane currents. Transcriptome analysis revealed TGF-β1-dependent changes in 29 of 63 ion channel/pump/connexin transcripts, indicating a pleiotropic effect on the electrical phenotype of myofibroblasts. Whereas not affecting cardiomyocyte membrane potentials and cardiomyocyte-cardiomyocyte gap junctional coupling, TGF-β1depolarized cardiomyocytes coupled to myofibroblasts by ≈20 mV and increased gap junctional coupling between myofibroblasts and cardiomyocytes >5-fold as reflected by elevated connexin 43 and consortin transcripts. TGF-β1-dependent cardiomyocyte depolarization resulted from electrotonic crosstalk with myofibroblasts as demonstrated by immediate normalization of cardiomyocyte electrophysiology after targeted disruption of coupled myofibroblasts and by cessation of ectopic activity of cardiomyocytes coupled to myofibroblasts during pharmacological gap junctional uncoupling. In cardiac fibrosis models exhibiting slow conduction and ectopic activity, block of TGF-β1signaling completely abolished both arrhythmogenic conditions. Conclusions - TGF-β1profoundly alters the electrophysiological phenotype of cardiac myofibroblasts. Apart from possibly contributing to the control of cell function in general, the changes proved to be pivotal for proarrhythmic myofibroblast-cardiomyocyte crosstalk in vitro, which suggests that TGF-β1may play a potentially important role in arrhythmogenesis of the fibrotic heart.
TGF-β1(Transforming Growth Factor-β1) Plays a Pivotal Role in Cardiac Myofibroblast Arrhythmogenicity / Salvarani, Nicolã²; Maguy, Ange; De Simone, Stefano A.; Miragoli, Michele; Jousset, Florian; Rohr, Stephan. - In: CIRCULATION. ARRHYTHMIA AND ELECTROPHYSIOLOGY. - ISSN 1941-3149. - 10:5(2017), p. e004567. [10.1161/CIRCEP.116.004567]
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11381/2835492
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