Transforming growth factor-β and oxidative stress mediate tachycardia-induced cellular remodelling in cultured atrial-derived myocytes

Aims Atrial fibrillation (AF), a common tachyarrhythmia in clinical practice, is associated with increased oxidative stress. Structural remodelling in atrial myocytes, including myofibril degradation, is an important characteristic of AF. However, the mechanism underlying AF-induced cellular structural remodelling remains unclear. The aim of this study was to investigate the role of oxidative stress and related factors in tachycardia-induced atrial structural remodelling. Methods and results Cultured atrial-derived myocytes (HL-1 cell line) were subjected to electrical stimulation. Immunofluorescence and immunoblotting were used to evaluate oxidative stress, myofibril degradation, and transforming growth factor-beta (TGF-beta) expression. Tachypacing in HL-1 cells induced TGF-beta expression, pronounced oxidative stress including up-regulation of NADPH oxidases (Nox2/4), and myofibril degradation. Oxidative stress scavenger, NADPH oxidase inhibitors, and small-interfering RNAs for Nox2/4 blocked tachypacing-induced myofibril degradation, suggesting that Nox-derived oxidative stress may lead to tachycardia-induced myofibril degradation. Blockade of TGF-beta signalling by neutralizing TGF-beta antibodies attenuated myofibril loss in response to tachypacing, implicating autocrine and/or paracrine roles for TGF-beta in such effects. Tachypacing also induced the activation of p-Smad3 (an effective mediator of TGF-beta) and small-interfering RNAs for Nox2/4 attenuated its activation, supporting a crosstalk between both signalling pathways. Furthermore, TGF-beta expression, oxidative stress, and myofibril loss were greater in the atria of patients with AF than those with sinus rhythm. Conclusions Rapid activation in atrial myocytes promotes myofibril degradation through autocrine/paracrine TGF-beta signalling and increased oxidative stress. These findings provide an important mechanistic insight into AF-related structural remodelling.