Fibrosis entails the accumulation of excess extracellular matrix (ECM) components such as collagen. Excessive ECM deposition distorts normal tissue architecture, compromises cardiac pump function and disrupts cytoarchitecture of electrically coupled cardiomyocytes, predisposing to arrhythmias. Various triggers can promote cardiac fibrosis. Regardless of the initiating event, cardiac fibroblasts generally first proliferate and then differentiate into ECM-secreting myofibroblasts, the key mediators of fibrotic-tissue remodelling. Atria are more susceptible to fibrotic stimuli than ventricles, and fibrosis is important in atrial fibrillation (AF; Yue et al. 2011). Atrial-fibrotic remodelling causes conduction abnormalities and may promote electrical fibroblast–cardiomyocyte interactions that favour AF. While it is known that ECM-secreting myofibroblasts are central to atrial fibrosis formation, the precise regulatory mechanisms of fibroblast-to-myofibroblast transitions remain unclear (Wakili et al. 2011). A better understanding of the molecular biology underlying AF-promoting fibrosis may help to identify novel drugs for effective AF treatment (Dobrev et al. 2012).
Cardiac fibroblasts express ion channels (Du et al. 2010; Li et al. 2009) but their functional role is poorly understood. Recent studies have provided evidence that Ca2+-permeable melastatin type-7 transient-receptor potential (TRPM7) channels regulate human atrial fibroblast/myofibroblast function, potentially contri-buting to AF pathophysiology (Du et al. 2010). Ca2+-permeable TRP canonical-3 (TRPC3) channels control atrial fibroblast proliferation and differentiation by regulating the Ca2+ influx that activates ERK signalling. TRPC3-channel expression is increased in human AF, probably contributing to fibroblast-to-myofibroblast transition (Harada et al. 2011). Thus, TRPM7 and TRPC3 channels and the related Ca2+ influx may play important roles in AF-promoting fibrotic remodelling. However, whether voltage-gated ion channels also contribute to the activation of atrial myofibroblasts is unknown.
In a recent issue of The Journal of Physiology, Chatelier et al. (2012) demonstrate a unique de novo functional expression of Na+ currents in human atrial myofibroblasts. Human atrial fibroblasts did not show specific labelling for α-smooth muscle actin (α-SMA), an established marker of myofibroblasts, before 7 days in culture, but a strong staining after 12 days, indicating that the differentiation of fibroblasts into myofibroblasts occurred between 7 and 12 days of culture. The same time course was observed for expression of the Na+-channel subunit Nav1.5, with INa being recordable in every cell after 12 days in culture. RT-qPCR, immunofluorescence and pharmacological experiments showed that INa is predominantly conducted by Nav1.5.
The most common method to identify myofibroblasts is immunostaining for α-SMC. One important merit of the work of Chatelier et al. (2012), which is the first to show INa in human atrial myofibroblasts, is the identification of INa as a potential marker of human atrial myofibroblasts, which should foster the electrophysiological separation of fibroblasts and myofibroblasts in diseased human atria. They also add INa to the growing list of ion channels potentially controlling the transition of fibroblasts to ECM-secreting myofibroblasts. Ca2+-handling abnormalities are critical determinants of atrial cardiomyocyte dysfunction in AF (Voigt et al. 2012), and abnormal Ca2+ entry is suggested to be essential for fibroblast proliferation, migration and differentiation into myofibroblasts in diseased hearts (Yue et al. 2011). Fibroblasts lack voltage-gated Ca2+ channels and Ca2+ influx is likely to occur predominantly via TRPM7 and TRPC3 channels. In addition, reverse-mode (Ca2+ influx) Na+–Ca2+ exchanger (NCX) may also participate in Ca2+ signalling in myofibroblasts. Myofibroblast INa had a greater window current than cardiomyocyte INa, which should produce a larger persistent Na+ entry, enhancing Ca2+ influx through NCX that may contribute to cell proliferation. However, whether INa participates in the regulation of Ca2+ fluxes in myofibroblasts needs exploration.
Taken together, the work of Chatelier et al. (2012) opens new avenues in the understanding of voltage-gated ion channels in the molecular biology of myofibroblasts in the human atrium. Their study raises several important questions that need addressing in subsequent work. What is the source (endothelial cells?) of myofibroblasts de novo expressing Na+ channels? Do Na+ channels promote fibroblasts differentiation into myofibroblasts? Is ion-channel composition of fibroblasts and myofibroblasts different? Do Na+ channels accelerate myofibroblast proliferation, migration and secretion properties? Is the inhibition of Na+ channels in myofibroblasts an exploitable therapeutic strategy for AF? Answers to these questions should provide important insights into the multifunctional role of ion channels in cardiac myofibroblasts and their precise role in structural remodelling in AF.