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European Journal of Heart Failure 2004 6(2):137-144; doi:10.1016/j.ejheart.2003.10.007
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© 2003 European Society of Cardiology

Suppression of cytokines and nitric oxide production, and protection against lethal endotoxemia and viral myocarditis by a new NF-{kappa}B inhibitor

Akira Matsumoria,*, Youichi Nunokawab, Akira Yamakib, Kanjo Yamamotoa, Myung-Woo Hwanga, Tadashi Miyamotoa, Masatake Haraa, Ryosuke Nishioa, Katsura Kitaura-Inenagaa and Koh Onoa

a Department of Cardiovascular Medicine Kyoto University Graduate School of Medicine, 54 Kawahara-cho Shogoin, Sakyo-ku, Kyoto 606-8397, Japan
b Suntory Biomedical Research Limited Japan

* Corresponding author. Present address: Daiichi-Suntory Biomedical Research Limited, Osaka, 618-8513, Japan. Tel.: +81-75-751-3186; fax: +81-75-751-6477. E-mail address: amat{at}kuhp.kyoto-u.ac.jp


  Abstract

Background: Nuclear factor kappa B (NF-{kappa}B) is activated by several factors, which increase the inflammatory response, and this activation, in turn, leads to the expression of several genes such as cytokines, and may play an important role in cardiovascular diseases.

Aims: The aim of the study is to examine the effect of SUN C8079, a newly synthesized NF-{kappa}B inhibitor in vitro and in vivo.

Methods: We examined the effects of SUN C8079 on the transcriptional responses of NF-{kappa}B, on activation of NF-{kappa}B in electrophoretic mobility shift assay, and on the gene expressions of tumor necrosis factor (TNF)-{alpha} and iNOS. We also studied effects of SUN C8079 on lethal endotoxemia and viral myocarditis in mice.

Results: SUN C8079 inhibited the lipopolysaccharide (LPS)-induced expression of the genes of TNF-{alpha} and iNOS by inhibiting the activation of NF-{kappa}B in vitro. SUN C8079 inhibited the systemic release of TNF-{alpha} and improved mortality in LPS-treated mice. In addition to protecting mice against lethal endotoxemia, SUN C8079 prevented the development of myocarditis due to the encephalomyocarditis virus (EMCV), and inhibited the expressions of proinflammatory cytokines and the iNOS gene in cardiac tissues.

Conclusion: These findings suggest that the activation of NF-{kappa}B plays an important role in the pathogenesis of endotoxemia and viral myocarditis, and that the NF-{kappa}B inhibitor, SUN C8079, may be therapeutic in these disorders.

Key Words: Nuclear factor kappa B • Tumor necrosis factor • Cytokines • Inducible nitric oxide synthase • Endotoxemia • Myocarditis

Received May 16, 2003; Revised July 28, 2003; Accepted October 8, 2003


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