Blockade of NF-kappaB improves cardiac function and survival without affecting inflammation in TNF-alpha-induced cardiomyopathy.
OBJECTIVE
NF-kappaB, 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-kappaB.


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-kappaB, transgenic mice (TG/p50(+/+)) were crossed with knockout mice in which the p50 subunit of NF-kappaB was disrupted (WT/p50(-/-)).


RESULTS
The electrophoretic mobility shift assay demonstrated that NF-kappaB 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.


CONCLUSIONS
Blockade of NF-kappaB activation did not ameliorate myocardial inflammation but improved cardiac function and survival in male TNF-alpha TG mice. An inhibition of NF-kappaB may be a new therapeutic strategy for cardiac remodeling and heart failure, especially when proinflammatory cytokines are activated.
Kawamura
Natsumi
N
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Higashi-ku, Fukuoka, Japan.
Kubota
Toru
T
Kawano
Shunichi
S
Monden
Yoshiya
Y
Feldman
Arthur M
AM
Tsutsui
Hiroyuki
H
Takeshita
Akira
A
Sunagawa
Kenji
K
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D009202:Cardiomyopathies / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D024202:Electrophoretic Mobility Shift Assay; D005818:Genetic Engineering; D008264:Macrophages / Q000276:immunology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000032:analysis / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009206:Myocardium / Q000276:immunology / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D020257:Ventricular Remodeling
D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D020780:Matrix Metalloproteinase 9