Soluble TNF receptors prevent apoptosis in infiltrating cells and promote ventricular rupture and remodeling after myocardial infarction

Yoshiya Monden, Toru Kubota, Takaki Tsutsumi, Takahiro Inoue, Shunichi Kawano, Natsumi Kawamura, Tomomi Ide, Kensuke Egashira, Hiroyuki Tsutsui, Kenji Sunagawa

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

Abstract

Objective: Tumor necrosis factor (TNF)-α 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-α 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-α, 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-α 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-α may play not only toxic but also protective roles in MI.

Original languageEnglish
Pages (from-to)794-805
Number of pages12
JournalCardiovascular research
Volume73
Issue number4
DOIs
Publication statusPublished - Mar 1 2007

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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