TY - JOUR
T1 - Soluble tumor necrosis factor receptor abrogates myocardial inflammation but not hypertrophy in cytokine-induced cardiomyopathy
AU - Kubota, Toru
AU - Bounoutas, George S.
AU - Miyagishima, Masayuki
AU - Kadokami, Toshiaki
AU - Sanders, Virginia J.
AU - Bruton, Christina
AU - Robbins, Paul D.
AU - McTiernan, Charles F.
AU - Feldman, Arthur M.
PY - 2000/5/30
Y1 - 2000/5/30
N2 - Background - Transgenic mice with cardiac-specific overexpression of tumor necrosis factor (TNF)-α develop dilated cardiomyopathy. The present study was designed to evaluate therapeutic effects of adenovirus-mediated neutralization of TNF-α on this model. Methods and Results - An adenovirus encoding the 55-kDa TNF receptor-IgG fusion protein (AdTNFRI) was injected intravenously into 6-week-old transgenic mice, which resulted in high levels of TNFRI in both plasma and myocardium. AdTNFRI did not reverse cardiomegaly but abrogated myocardial inflammation. Furthermore, AdTNFRI blocked the myocardial expression of intercellular adhesion molecule-1 and downstream cytokines, including interleukin-1β and monocyte chemotactic protein-1. Downregulation of α-myosin heavy chain was restored by the treatment, whereas upregulation of β-myosin heavy chain was not reversed. In contrast, the downregulation of sarcoplasmic reticulum Ca2+-ATPase and phospholamban was normalized by AdTNFRI. Echocardiographic measurements showed that left ventricular end-systolic diameter was significantly larger in transgenic mice than in control mice, and this increase was reversed by the AdTNFRI treatment. However, left ventricular wall thickening was not reversed. Conclusions - These results suggest that anti-TNF therapy may hold promise in the treatment of end-stage heart failure.
AB - Background - Transgenic mice with cardiac-specific overexpression of tumor necrosis factor (TNF)-α develop dilated cardiomyopathy. The present study was designed to evaluate therapeutic effects of adenovirus-mediated neutralization of TNF-α on this model. Methods and Results - An adenovirus encoding the 55-kDa TNF receptor-IgG fusion protein (AdTNFRI) was injected intravenously into 6-week-old transgenic mice, which resulted in high levels of TNFRI in both plasma and myocardium. AdTNFRI did not reverse cardiomegaly but abrogated myocardial inflammation. Furthermore, AdTNFRI blocked the myocardial expression of intercellular adhesion molecule-1 and downstream cytokines, including interleukin-1β and monocyte chemotactic protein-1. Downregulation of α-myosin heavy chain was restored by the treatment, whereas upregulation of β-myosin heavy chain was not reversed. In contrast, the downregulation of sarcoplasmic reticulum Ca2+-ATPase and phospholamban was normalized by AdTNFRI. Echocardiographic measurements showed that left ventricular end-systolic diameter was significantly larger in transgenic mice than in control mice, and this increase was reversed by the AdTNFRI treatment. However, left ventricular wall thickening was not reversed. Conclusions - These results suggest that anti-TNF therapy may hold promise in the treatment of end-stage heart failure.
KW - Genes
KW - Hormones
KW - Viruses
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U2 - 10.1161/01.CIR.101.21.2518
DO - 10.1161/01.CIR.101.21.2518
M3 - Article
C2 - 10831527
AN - SCOPUS:0034738142
SN - 0009-7322
VL - 101
SP - 2518
EP - 2525
JO - Circulation
JF - Circulation
IS - 21
ER -