(Circulation. 2000;101:2518.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Soluble Tumor Necrosis Factor Receptor Abrogates Myocardial Inflammation but Not Hypertrophy in Cytokine-Induced Cardiomyopathy
From the Cardiovascular Institute (T. Kubota, G.S.B., T. Kadokami, C.F.M., A.M.F.), Department of Surgery (M.M.), Division of Neuropathology (V.J.S.), and Department of Molecular Genetics and Biochemistry (C.B., P.D.R.), University of Pittsburgh Medical Center, Pittsburgh, Pa.
Correspondence to Arthur M. Feldman, MD, PhD, 200 Lothrop St, S 572 Scaife Hall, Pittsburgh, PA 15213. E-mail feldmanam{at}msx.upmc.edu
Background—Transgenic mice with
cardiac-specific overexpression of tumor necrosis factor (TNF)-
develop dilated cardiomyopathy. The present
study was designed to evaluate therapeutic effects of
adenovirus-mediated neutralization of TNF- 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-1ß and monocyte
chemotactic protein-1. Downregulation of -myosin heavy chain was
restored by the treatment, whereas upregulation of ß-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.
Key Words: viruses • genes • hormones
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