Soluble TNF receptors prevent apoptosis in infiltrating cells and promote ventricular rupture and remodeling after myocardial infarction.
OBJECTIVE
Tumor necrosis factor (TNF)-alpha induced in damaged myocardium has been considered to be cardiotoxic. However, the negative results of RENEWAL and ATTACH prompt us to reconsider the role of TNF-alpha in cardiovascular diseases. The present study aimed to evaluate the effects of soluble TNF receptor treatment on myocardial infarction (MI).


METHODS
An adenovirus encoding a 55-kDa TNF receptor-IgG fusion protein (AdTNFR1) was used to neutralize TNF-alpha, and an adenovirus encoding LacZ (AdLacZ) served as control. In the pre-MI treatment protocol, mice were given an intravenous injection of AdTNFR1 or AdLacZ 1 week before left coronary artery ligation to induce MI. In the post-MI treatment protocol, mice were treated with AdTNFR1 or AdLacZ 1 week after left coronary ligation.


RESULTS
Treatment with AdTNFR1 neutralized bioactivity of TNF-alpha that was activated after MI and prevented apoptosis of infiltrating cells in infarct myocardium. However, pre-MI treatment with AdTNFR1 promoted ventricular rupture by reducing fibrosis with further activation of matrix metalloproteinase (MMP)-9. Post-MI treatment with AdTNFR1 exacerbated ventricular dysfunction and remodeling, with enhanced fibrosis of non-infarct myocardium with further MMP-2 activation.


CONCLUSIONS
Both pre- and post-MI treatments with AdTNFR1 were deleterious in a mouse MI model. Thus, TNF-alpha may play not only toxic but also protective roles in MI.
Monden
Yoshiya
Y
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Kubota
Toru
T
Tsutsumi
Takaki
T
Inoue
Takahiro
T
Kawano
Shunichi
S
Kawamura
Natsumi
N
Ide
Tomomi
T
Egashira
Kensuke
K
Tsutsui
Hiroyuki
H
Sunagawa
Kenji
K
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D005355:Fibrosis; D005822:Genetic Vectors / Q000008:administration & dosage; D006342:Heart Rupture, Post-Infarction / Q000378:metabolism* / Q000473:pathology; D020287:In Situ Nick-End Labeling; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000032:analysis / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000032:analysis / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D014161:Transduction, Genetic / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D017725:Ventricular Pressure; D020257:Ventricular Remodeling
D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9