title: Molecular basis of selective atrial fibrosis due to overexpression of transforming growth factor-β1.
abstract: OBJECTIVE
  Animal studies show that transforming growth factor-β1 (TGF-β1) is an important mediator of atrial fibrosis and atrial fibrillation (AF). This study investigated the role of TGF-β1 in human AF and the mechanism of atrial-selective fibrosis.
  
  
  RESULTS
  Atrial specimens from 17 open heart surgery patients and left atrial and ventricular specimens from 17 explanted hearts were collected to assess the relationship between TGF-β1, AF, and differential atrial vs. ventricular TGF-β1 levels. A transgenic mouse model overexpressing active TGF-β1 was used to study the mechanisms underlying the resultant atrial-selective fibrosis. Higher right atrial total TGF-β1 levels (2.58 ± 0.16-fold, P < 0.0001) and active TGF-β1 (3.7 ± 0.7-fold, P = 0.013) were observed in those that developed post-operative AF. Although no ventricular differences were observed, 11 explanted heart failure hearts exhibited higher atrial TGF-β1 levels than 6 non-failing hearts (2.30 ± 0.87 fold higher, P < 0.001). In the transgenic mouse, TGF-β1 receptor-1 kinase blockade resulted in decreased atrial expression of fibrosis-related genes. By RNA microarray analyses in that model, 80 genes in the atria and only 2 genes in the ventricle were differentially expressed. Although these mice atria, but not the ventricles, exhibited increased expression of fibrosis-related genes and phosphorylation of Smad2, there were no differences in TGF-β1 receptor levels or Smads in the atria compared with the ventricles.
  
  
  CONCLUSIONS
  TGF-β1 mediates selective atrial fibrosis in AF that occurs via TGF-β Receptor 1/2 and the classical Smad pathway. The differential atrial vs. ventricular fibrotic response occurs at the level of TGF-β1 receptor binding or phosphorylation.
authors.affiliation: Division of Cardiology, University of California, San Francisco, CA 94143, USA.
authors.forename: Dolkun
authors.initials: D
authors.lastname: Rahmutula
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Marcus
authors.forename: Emily E
authors.initials: EE
authors.lastname: Wilson
authors.forename: Chun-Hua
authors.initials: CH
authors.lastname: Ding
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Xiao
authors.forename: Agnes C
authors.initials: AC
authors.lastname: Paquet
authors.forename: Rebecca
authors.initials: R
authors.lastname: Barbeau
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Barczak
authors.forename: David J
authors.initials: DJ
authors.lastname: Erle
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Olgin
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000209:etiology*; D005355:Fibrosis; D006325:Heart Atria / Q000473:pathology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008907:Mink; D018125:Receptors, Transforming Growth Factor beta / Q000032:analysis; D053773:Transforming Growth Factor beta1 / Q000032:analysis / Q000502:physiology*
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1
keywords: Atrial fibrillation; Cardiac fibrosis; Gene expression; Heart failure; Transforming growth factor-beta1