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


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.
Research and Development Unit, National Heart Centre Singapore, Singapore. reginald.liew@gmail.com
Reginald
R
Liew
Katwadi
K
Khairunnisa
Yacui
Y
Gu
Nicole
N
Tee
New Oo
NO
Yin
Tin Maung
TM
Naylynn
Kyaw Thu
KT
Moe
D000199:Actins / Q000378:metabolism; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016275:Atrial Function / Q000187:drug effects; D018031:Connexin 43 / Q000378:metabolism; D017630:Connexins / Q000378:metabolism; D015536:Down-Regulation; D005355:Fibrosis; D005455:Fluorescent Antibody Technique; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007275:Injections, Intravenous; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D051900:Smad3 Protein / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000633:toxicity*; D000097003:Gap Junction alpha-5 Protein
D000199:Actins; D018031:Connexin 43; D017630:Connexins; D020778:Matrix Metalloproteinase 2; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D000097003:Gap Junction alpha-5 Protein; C543076:GJA1 protein, mouse; C497791:Smad3 protein, mouse; C544013:alpha-smooth muscle actin, mouse; C522362:Mmp2 protein, mouse