title: Transforming growth factor-β and oxidative stress mediate tachycardia-induced cellular remodelling in cultured atrial-derived myocytes.
abstract: OBJECTIVE
  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.
  
  
  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-β (TGF-β) expression. Tachypacing in HL-1 cells induced TGF-β 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-β signalling by neutralizing TGF-β antibodies attenuated myofibril loss in response to tachypacing, implicating autocrine and/or paracrine roles for TGF-β in such effects. Tachypacing also induced the activation of p-Smad3 (an effective mediator of TGF-β) and small-interfering RNAs for Nox2/4 attenuated its activation, supporting a crosstalk between both signalling pathways. Furthermore, TGF-β 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-β signalling and increased oxidative stress. These findings provide an important mechanistic insight into AF-related structural remodelling.
authors.affiliation: First Cardiovascular Division, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Fu-Shin Road no 5, Kwei-Shan, Tao-Yuan 333, Taiwan.
authors.forename: Yung-Hsin
authors.initials: YH
authors.lastname: Yeh
authors.forename: Chi-Tai
authors.initials: CT
authors.lastname: Kuo
authors.forename: Ting-Hsiang
authors.initials: TH
authors.lastname: Chan
authors.forename: Gwo-Jyh
authors.initials: GJ
authors.lastname: Chang
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Qi
authors.forename: FengChun
authors.initials: F
authors.lastname: Tsai
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
authors.forename: Wei-Jan
authors.initials: WJ
authors.lastname: Chen
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001281:Atrial Fibrillation / Q000378:metabolism* / Q000473:pathology; D019898:Autocrine Communication; D015153:Blotting, Western; D002304:Cardiac Pacing, Artificial; D016022:Case-Control Studies; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D016166:Free Radical Scavengers / Q000494:pharmacology; D006325:Heart Atria / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009210:Myofibrils / Q000378:metabolism / Q000473:pathology; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D019899:Paracrine Communication; D034622:RNA Interference; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D013617:Tachycardia, Supraventricular / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D057134:Antibodies, Neutralizing; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D008562:Membrane Glycoproteins; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse