Both pre- and post-MI treatments with AdTNFR1 were deleterious in a mouse MI model, promoting ventricular rupture or exacerbating ventricular dysfunction and remodeling.
Does soluble TNF receptor treatment prevent adverse outcomes in a mouse model of myocardial infarction?
Neutralization of TNF-alpha via soluble TNF receptors is deleterious in a mouse MI model, suggesting TNF-alpha plays a protective role post-MI, which may explain the failure of anti-TNF therapies in clinical trials.
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 et al. (Tue,) conducted a other in Myocardial infarction. AdTNFR1 (adenovirus encoding a 55-kDa TNF receptor-IgG fusion protein) vs. AdLacZ (adenovirus encoding LacZ) was evaluated on Ventricular rupture, remodeling, and dysfunction. Both pre- and post-MI treatments with AdTNFR1 were deleterious in a mouse MI model, promoting ventricular rupture or exacerbating ventricular dysfunction and remodeling.