Role of tumor necrosis factor-α in the pathogenesis of atrial fibrosis and development of an arrhythmogenic substrate

Circ J. 2013;77(5):1171-9. doi: 10.1253/circj.cj-12-1155. Epub 2013 Feb 1.

Abstract

Background: Although tumor necrosis factor-α (TNF-α) levels are increased in patients with atrial fibrillation (AF), its role in the pathogenesis of AF is unclear. We investigated whether direct delivery of TNF-α could induce atrial fibrosis.

Methods and results: TNF-α (4 μg/kg) was injected into the tail vein of 20 male Swiss albino mice (TNF group) and saline into 20 control mice (CON group). The dose was carefully chosen to avoid any significant decrease in left ventricular (LV) function. Animals were killed after 16 weeks and their atria examined for fibrosis. We found increased atrial fibrosis in the TNF group compared with the CON group [372.8±21.5 arbitrary units (a.u.) vs. 56.9±6.5 a.u., respectively, mean±SEM; P<0.0001] and decreased connexin-40 immunofluorescence [7.5±0.4 a.u vs. 40.4±1.9 a.u, respectively; P<0.0001]. Transforming growth factor-β [TGF-β: 95.6±1.8 a.u vs. 29.4±5.8 a.u; P<0.001], α-smooth muscle actin (α-SMA: 97.9±13.0 a.u vs. 50.1±18.5 a.u; P<0.05] and matrix metalloproteinase 2 (MMP-2)/GAPDH levels [157.3±26.4 a.u vs. 105.8±13.3 a.u; P<0.05] were also increased in the TNF group.

Conclusions: TNF-α is involved in the pathogenesis of atrial fibrosis and altered connexin-40 expression in mice through the TGF-β signaling pathway, activation of myofibroblasts and increased secretion of MMPs. Collectively, these changes may contribute to the arrhythmogenic substrate and development of AF.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Arrhythmias, Cardiac / chemically induced*
  • Arrhythmias, Cardiac / metabolism
  • Arrhythmias, Cardiac / pathology
  • Arrhythmias, Cardiac / physiopathology
  • Atrial Function* / drug effects
  • Connexin 43 / metabolism
  • Connexins / metabolism
  • Down-Regulation
  • Fibrosis
  • Fluorescent Antibody Technique
  • Heart Atria / drug effects
  • Heart Atria / metabolism
  • Heart Atria / pathology
  • Heart Atria / physiopathology
  • Injections, Intravenous
  • Male
  • Matrix Metalloproteinase 2 / metabolism
  • Mice
  • Myofibroblasts / drug effects
  • Myofibroblasts / metabolism
  • Myofibroblasts / pathology
  • Signal Transduction / drug effects
  • Smad3 Protein / metabolism
  • Time Factors
  • Transforming Growth Factor beta / metabolism
  • Tumor Necrosis Factor-alpha / administration & dosage
  • Tumor Necrosis Factor-alpha / toxicity*

Substances

  • Actins
  • Connexin 43
  • Connexins
  • GJA1 protein, mouse
  • Smad3 Protein
  • Smad3 protein, mouse
  • Transforming Growth Factor beta
  • Tumor Necrosis Factor-alpha
  • alpha-smooth muscle actin, mouse
  • connexin 40
  • Matrix Metalloproteinase 2
  • Mmp2 protein, mouse