title: Soluble TNF receptors prevent apoptosis in infiltrating cells and promote ventricular rupture and remodeling after myocardial infarction.
abstract: 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.
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Monden
authors.forename: Toru
authors.initials: T
authors.lastname: Kubota
authors.forename: Takaki
authors.initials: T
authors.lastname: Tsutsumi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Inoue
authors.forename: Shunichi
authors.initials: S
authors.lastname: Kawano
authors.forename: Natsumi
authors.initials: N
authors.lastname: Kawamura
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ide
authors.forename: Kensuke
authors.initials: K
authors.lastname: Egashira
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsutsui
authors.forename: Kenji
authors.initials: K
authors.lastname: Sunagawa
mesh_terms: 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
chemical_list: D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9