title: Nicotinamide adenine dinucleotide phosphate oxidase 4 mediates the differential responsiveness of atrial versus ventricular fibroblasts to transforming growth factor-β.
abstract: BACKGROUND
  Atrial fibrosis, a common feature of atrial fibrillation, is thought to originate from the differential response of atrium versus ventricle to pathological insult. However, detailed mechanisms underlying the regional differences remain unclear. The aim of this study was to investigate the related factor(s) in mediating atrial vulnerability to fibrotic processes.
  
  
  RESULTS
  We first compared the response of cultured atrial versus ventricular fibroblasts with transforming growth factor-β (TGF-β), a key mediator of myocardial fibrosis. Atrial fibroblasts showed a stronger response to TGF-β1 in producing extracellular matrix protein (collagen and fibronectin) than ventricular fibroblasts. Furthermore, TGF-β1 activated its downstream signaling (Smads) and induced pronounced oxidative stress, including up-regulation of nicotinamide adenine dinucleotide phosphate oxidase in atrial fibroblasts, and to a lesser extent in ventricular fibroblasts. Nicotinamide adenine dinucleotide phosphate oxidase inhibitors and small-interfering RNA for Nox4 eliminated TGF-β-induced difference between atrial and ventricular fibroblasts, suggesting the crucial role of Nox4 in mediating the atrial-ventricular discrepancy. Small-interfering RNA for Smad3 also suppressed the differential responsiveness of atrial versus ventricular fibroblasts to TGF-β1, including Nox4 activation, implicating a crosstalk between nicotinamide adenine dinucleotide phosphate oxidases and Smad. In vivo, the increased TGF-β1 responsiveness and Nox4 expression were documented in the atria of transgenic mice with cardiac overexpression of TGF-β1.
  
  
  CONCLUSIONS
  Atrial fibroblasts show greater fibrotic and oxidative responses to TGF-β1 than ventricular fibroblasts. Nox4-derived reactive oxygen species production mediates the susceptibility of atrial fibroblasts to TGF-β1 via activating TGF-β1/Smad signaling cascade, which provides a novel insight into the pathogenesis of atrial fibrosis.
authors.affiliation: First Cardiovascular Division, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Kuei-Shan, Taoyuan, Taiwan.
authors.forename: Yung-Hsin
authors.initials: YH
authors.lastname: Yeh
authors.forename: Chi-Tai
authors.initials: CT
authors.lastname: Kuo
authors.forename: Gwo-Jyh
authors.initials: GJ
authors.lastname: Chang
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Qi
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
authors.forename: Wei-Jan
authors.initials: WJ
authors.lastname: Chen
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004789:Enzyme Activation; D005347:Fibroblasts / Q000201:enzymology* / Q000473:pathology; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D006325:Heart Atria / Q000201:enzymology / Q000473:pathology; D006352:Heart Ventricles / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D034622:RNA Interference; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D020257:Ventricular Remodeling
chemical_list: D005353:Fibronectins; D051900:Smad3 Protein; C497787:Smad3 protein, rat; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D003094:Collagen; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; C498911:Nox4 protein, rat
keywords: NADPH oxidase; TGF; atrial fibrillation; atrial fibrosis; oxidative stress