Ca 2+ Entry Through TRP-C Channels Regulates Fibroblast Biology in Chronic Atrial Fibrillation

Abstract

In this issue of Circulation , Harada et al1 provide fundamental new insights into the cellular mechanism(s) for initiation and maintenance of chronic atrial fibrillation in the human heart. The authors, taking what most might still consider to be an unconventional approach to understanding this proarrhythmic substrate,2,3,4 have identified the atrial fibroblast as an important player. More specifically, this international group of investigators concludes that a particular member of the transient receptor potential or TRP family5 of ion channels, TRPC3, when expressed/upregulated in human atrial fibroblasts, can contribute to chronic atrial fibrillation. Activation or enhanced expression of TRPC3 provides a means for increased transmembrane calcium entry into the fibroblast. This trigger calcium can then result in a marked increase in proliferation, followed by transformation to the myofibroblast phenotype.6,7 A previous study had drawn attention to the possibility that a different TRP channel subtype, TRPM7, could play a somewhat similar proarrhythmic role in the atrium.7,8 Article see p 2051 Atrial fibrillation is the most common form of cardiac arrhythmia in adult humans.9 Importantly, its incidence is projected to increase substantially as a consequence of the association of atrial fibrillation with healthy aging,10 diabetes mellitus, and hypothyroidism. Harada et al1 provide the first evidence for the presence of TRPC3 current during the proliferative phase in cultured human atrial fibroblasts. Knockdown of TRPC3 is able to suppress atrial fibroblast proliferation, and similar results were obtained with the pharmacological inhibitor PYR3, a relatively new pyrazole-based compound. This particular TRP channel exhibits significant calcium permeability. This calcium influx contributes to ERK phosphorylation, which is involved in mediating atrial fibroblast proliferation. A very interesting observation …