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

doi:10.1016/j.cardiores.2006.12.016

Cardiovascular Research 2007 73(4):794-805; doi:10.1016/j.cardiores.2006.12.016

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

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

^aDepartment of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
^bDepartment of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo 060-8638, Japan

^* Corresponding author. Tel.: +81 92 642 5359; fax: +81 92 642 5374. Email address: kubotat{at}cardiol.med.kyushu-u.ac.jp

Objective: Tumor necrosis factor (TNF)- ${alpha}$ induced in damaged myocardiumhas been considered to be cardiotoxic. However, the negativeresults of RENEWAL and ATTACH prompt us to reconsider the roleof TNF- ${alpha}$ in cardiovascular diseases. The present study aimedto evaluate the effects of soluble TNF receptor treatment onmyocardial infarction (MI).

Methods: An adenovirus encoding a 55-kDa TNF receptor-IgG fusionprotein (AdTNFR1) was used to neutralize TNF- ${alpha}$ , and an adenovirusencoding LacZ (AdLacZ) served as control. In the pre-MI treatmentprotocol, mice were given an intravenous injection of AdTNFR1or AdLacZ 1 week before left coronary artery ligation toinduce MI. In the post-MI treatment protocol, mice were treatedwith 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 infiltratingcells in infarct myocardium. However, pre-MI treatment withAdTNFR1 promoted ventricular rupture by reducing fibrosis withfurther activation of matrix metalloproteinase (MMP)-9. Post-MItreatment with AdTNFR1 exacerbated ventricular dysfunction andremodeling, with enhanced fibrosis of non-infarct myocardiumwith further MMP-2 activation.

Conclusions: Both pre- and post-MI treatments with AdTNFR1 weredeleterious in a mouse MI model. Thus, TNF- ${alpha}$ may play not onlytoxic but also protective roles in MI.

KEYWORDS Apoptosis; Cytokines; Infarction; Matrix metalloproteinases; Remodeling

Time for primary review 27 days

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