Blockade of NF-kappaB improves cardiac function and survival without affecting inflammation in TNF-alpha-induced cardiomyopathy.
Blockade of NF-kappaB improves cardiac function and survival without affecting inflammation in TNF-alpha-induced cardiomyopathy.
复制标题
DOI：
--
复制
发表时间：
2005
影响因子：
10.8
通讯作者：
Natsumi Kawamura;T. Kubota;Shunichi Kawano;Yoshiya Monden;A. Feldman;H. Tsutsui;A. Takeshita;K. Sunagawa
中科院分区：
文献类型：
--
作者：
Natsumi Kawamura;T. Kubota;Shunichi Kawano;Yoshiya Monden;A. Feldman;H. Tsutsui;A. Takeshita;K. Sunagawa
目的NF-κ B是调节炎症过程的关键转录因子，在衰竭的人心脏中被激活，促炎细胞因子的表达增强。在本研究中，我们评估了这一假设，即促炎细胞因子的心脏毒性作用是由NF-κ B的激活介导的。方法采用心肌特异性过表达TNF-α的转基因小鼠作为苦参碱诱导的心肌病模型。为了阻断NF-κ B的活化，将转基因小鼠（TG/p50（+/+））与NF-κ B的p50亚基被破坏的敲除小鼠（WT/p50（-/-））杂交。结果电泳迁移率改变实验显示TG/p50（+/+）小鼠心肌NF-κ B被激活，而TG/p50（-/-）小鼠心肌NF-κ B被完全抑制。雄性TG小鼠死于充血性心力衰竭早于雌性，其中p50亚基的破坏显著改善了存活率。与TG/p50（+/+）小鼠相比，TG/p50（-/-）小鼠心室扩张和肥大明显减少，缩短率保持不变。虽然TG/p50（-/-）小鼠心肌促炎细胞因子的表达或炎性细胞浸润不受影响，但MMP-9的表达和活性的增加在TG/p50（-/-）小鼠中被显著抑制。结论：阻断NF-κ B活化不能改善TNF-α TG雄性小鼠的心肌炎症，但能改善心功能和存活率。抑制NF-κ B可能是心脏重塑和心力衰竭的一种新的治疗策略，特别是当促炎细胞因子被激活时。
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. CONCLUSION 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.