Piezo1 and BK_Ca channels in human atrial fibroblasts: interplay and remodelling in atrial fibrillation

Abstract

AimsAtrial Fibrillation (AF) is an arrhythmia of increasing prevalence in the aging population of developed countries. One of the important indicators of AF is sustained atrial dilatation, highlighting the importance of mechanical overload in the pathophysiology of AF. The mechanisms by which atrial cells, including fibroblasts, sense and react to changing mechanical forces, are not fully elucidated. Here, we characterise stretch-activated ion channels (SAC) in human atrial fibroblasts and changes in SAC-presence and -activity associated with AF.Methods and ResultsUsing primary cultures of human atrial fibroblasts, isolated from patients in sinus rhythm or sustained AF, we combine electrophysiological, molecular and pharmacological tools to identify SAC. Two electrophysiological SAC-signatures were detected, indicative of cation-nonselective and potassium-selective channels. Using siRNA-mediated knockdown, we identified the nonselective SAC as Piezo1. Biophysical properties of the potassium-selective channel, its sensitivity to calcium, paxilline and iberiotoxin (blockers), and NS11021 (activator), indicated presence of calcium-dependent ‘big potassium channels’, BKCa. In cells from AF patients, Piezo1 activity and mRNA expression levels were higher than in cells from sinus rhythm patients, while BKCa activity (but not expression) was downregulated. Both Piezo1-knockdown and removal of extracellular calcium from the patch pipette resulted in a significant reduction of BKCa current during stretch. No co-immunoprecipitation of Piezo1 and BKCa was detected.ConclusionsHuman atrial fibroblasts contain at least two types of ion channels that are activated during stretch: Piezo1 and BKCa. While Piezo1 is directly stretch-activated, the increase in BKCa activity during mechanical stimulation appears to be mainly secondary to calcium influx via SAC such as Piezo1. During sustained AF, Piezo1 is increased, while BKCa activity is reduced, highlighting differential regulation of both channels. Our data support the presence and interplay of Piezo1 and BKCa in human atrial fibroblasts in the absence of physical interactions between the two channel proteins.

Omega-3 fatty acids and atrial fibrillation

“…Other atrial cell types, such as fibroblasts, may also express mechanical stress-related signaling through the PIEZO1 channels. Atrial fibroblasts from patients with AF have higher PIEZO1 expression levels and activity than those from patients with sinus rhythm, indicating that PIEZO1 may promote atrial structural remodeling [30]. A pro-arrhythmic environment may result from changes in voltage-gated ion channels, ionic pumps, cell surface receptors, and extracellular matrix-cytoskeletal interactions.…”

Fishing for Links Between Omega-3 Fatty Acids and Atrial Fibrillation

“…PIEZO1 expression levels and activity have been shown to increase in atrial fibroblasts from patients with AF compared with those from patients with sinus rhythm, suggesting that PIEZO1 might contribute to atrial structural remodeling. 5 The effects of omega-3 fatty acid on fibroblast functions in the context of PIEZO1 are yet to be investigated. Whether progressive myocardial stiffening caused by atrial fibrosis, hypertrophy, and extracellular matrix deposition might contribute to a dynamic feedback loop that modulates force propagation and PIEZO1 activation is unknown.…”