期刊
CARDIOVASCULAR RESEARCH
卷 66, 期 3, 页码 520-529出版社
OXFORD UNIV PRESS
DOI: 10.1016/j.cardiores.2005.02.007
关键词
nuclear factor-kappa B; cytokines; tumor necrosis factor-alpha; matrix metalloproteinases; transgenic animal models; myocarditis; heart failure; cardiac remodeling
Objective: NF-kappa B, a key transcription factor that regulates inflammatory processes, has been shown to be activated in the failing human heart with enhanced expression of proinflammatory cytokines. In the present study, we assessed the hypothesis that cardiotoxic effects of proinflammatory cytokines are mediated by the activation of NF-kappa B. Methods: Transgenic mice with cardiac-specific overexpression of TNF-alpha were used as a model of cytokine-induced cardiomyopathy. To block the activation of NF-kappa B, transgenic mice (TG/p50(+/+)) were crossed with knockout mice in which the p50 subunit of NF-kappa B was disrupted (WT/p50(-/-)). Results: The electrophoretic mobility shift assay demonstrated that NF-kappa B was activated in the myocardium of TG/p50(+/+) mice, while it was completely abolished in TG/p50(-/-) mice. Male TG mice died of congestive heart failure earlier than females, where the disruption of the p50 subunit significantly improved the survival. Compared with TG/p50(+/+) mice, TG/p50(-/-) mice showed a significant reduction of ventricular dilatation and hypertrophy with preserved fractional shortening. Although the myocardial expression of proinflammatory cytokines or infiltration of inflammatory cells was not affected, increased expression and activity of MMP-9 were significantly suppressed in TG/p50(-/-) mice. Conclusion: Blockade of NF-kappa B activation did not ameliorate myocardial inflammation but improved cardiac function and survival in mate TNF-alpha TG mice. An inhibition of NF-kappa B may be a new therapeutic strategy for cardiac remodeling and heart failure, especially when proinflammatory cytokines are activated. (c) 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
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