Blockade of NF-κB improves cardiac function and survival without affecting inflammation in TNF-α-induced cardiomyopathy

Natsumi Kawamura, Toru Kubota, Shunichi Kawano, Yoshiya Monden, Arthur M. Feldman, Hiroyuki Tsutsui, Akira Takeshita, Kenji Sunagawa

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Abstract

Objective: NF-κB, 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-κB. Methods: Transgenic mice with cardiac-specific overexpression of TNF-α were used as a model of cytokine-induced cardiomyopathy. To block the activation of NF-κB, transgenic mice (TG/p50+/+) were crossed with knockout mice in which the p50 subunit of NF-κB was disrupted (WT/p50-/-). Results: The electrophoretic mobility shift assay demonstrated that NF-κB 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-κB activation did not ameliorate myocardial inflammation but improved cardiac function and survival in male TNF-α TG mice. An inhibition of NF-κB may be a new therapeutic strategy for cardiac remodeling and heart failure, especially when proinflammatory cytokines are activated.

Original languageEnglish
Pages (from-to)520-529
Number of pages10
JournalCardiovascular research
Volume66
Issue number3
DOIs
Publication statusPublished - Jun 1 2005

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All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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