Selective cardiac fibroblast activation by enhanced Gq signaling prolonged cardiomyocyte action potential duration by 33% and Ca2+ transient duration by 98%, leading to proarrhythmogenic automaticity.
Selective activation of cardiac fibroblasts via Gq signaling in a 3-D microtissue environment alters cardiomyocyte electrophysiology and promotes proarrhythmogenic automaticity.
Cardiac fibroblasts (CFs) are known to regulate cardiomyocyte (CM) function in vivo and in two-dimensional in vitro cultures. This study examined the effect of CF activation on the regulation of CM electrical activity in a three-dimensional (3-D) microtissue environment. Using a scaffold-free 3-D platform with interspersed neonatal rat ventricular CMs and CFs, G q -mediated signaling was selectively enhanced in CFs by Gα q adenoviral infection before coseeding with CMs in nonadhesive hydrogels. After 3 days, the microtissues were analyzed by signaling assay, histological staining, quantitative PCR, Western blots, optical mapping with voltage- or Ca 2+ -sensitive dyes, and microelectrode recordings of CF resting membrane potential (RMP CF ). Enhanced G q signaling in CFs increased microtissue size and profibrotic and prohypertrophic markers. Expression of constitutively active Gα q in CFs prolonged CM action potential duration (by 33%) and rise time (by 31%), prolonged Ca 2+ transient duration (by 98%) and rise time (by 65%), and caused abnormal electrical activity based on depolarization-induced automaticity. Constitutive G q activation in CFs also depolarized RMP CF from –33 to −20 mV and increased connexin 43 and connexin 45 expression. Computational modeling confers that elevated RMP CF and increased cell-cell coupling between CMs and CFs in a 3-D environment could lead to automaticity. In conclusion, our data demonstrate that CF activation alone is capable of altering action potential and Ca 2+ transient characteristics of CMs, leading to proarrhythmic electrical activity. Our results also emphasize the importance of a 3-D environment where cell-cell interactions are prevalent, underscoring that CF activation in 3-D tissue plays a significant role in modulating CM electrophysiology and arrhythmias. NEW & NOTEWORTHY In a three-dimensional microtissue model, which lowers baseline activation of cardiac fibroblasts but enables cell-cell, paracrine, and cell-extracellular matrix interactions, we demonstrate that selective cardiac fibroblast activation by enhanced G q signaling, a pathophysiological trigger in the diseased heart, modulates cardiomyocyte electrical activity, leading to proarrhythmogenic automaticity.
Kofron et al. (Sat,) conducted a other in Arrhythmias. Gαq adenoviral infection was evaluated on Cardiomyocyte action potential duration and Ca2+ transient characteristics. Selective cardiac fibroblast activation by enhanced Gq signaling prolonged cardiomyocyte action potential duration by 33% and Ca2+ transient duration by 98%, leading to proarrhythmogenic automaticity.
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