Blockade of NF-kappaB using IkappaB alpha dominant-negative mice ameliorates cardiac hypertrophy in myotrophin-overexpressed transgenic mice.
Blockade of NF-kappaB using IkappaB alpha dominant-negative mice ameliorates cardiac hypertrophy in myotrophin-overexpressed transgenic mice.
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DOI：
10.1016/j.jmb.2008.05.076
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发表时间：
2008-09
影响因子：
5.6
通讯作者：
David C. Young;Z. Popović;W. Jones;Sudhiranjan Gupta
中科院分区：
文献类型：
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作者：
David C. Young;Z. Popović;W. Jones;Sudhiranjan Gupta
核因子-κB(NF-κB)是一种普遍存在的转录因子，在心脏肥厚和心力衰竭等疾病过程中，调节多种基因，包括炎症分子、巨噬细胞浸润因子、细胞黏附分子等。此前，我们已经证明，在肌营养素诱导的心肌肥厚、自发性高血压大鼠和扩张型心肌病患者中，需要激活NF-κB。此外，我们最近使用肌营养素过表达转基因小鼠(MYO-TG)模型的研究表明，短发夹状RNA介导的NF-κB基因敲除显著减少了与改善心功能相关的心脏质量。尽管已有研究表明，NF-κB在心血管重塑中有重要作用，但持续阻断NF-κB是否在心血管重塑中有效尚不清楚。为了解决这个问题，我们采用了遗传方法，使用IκBα三重突变小鼠(3M)与MYO-TG小鼠(一种进行性肥大/心力衰竭模型)杂交。与24周龄的MYO-Tg小鼠相比，双转基因小鼠(MYO-3M)在24周龄时表现出心肌肥厚减轻(9.8±0.62vs5.4±0.34，p<；0.001)，心功能得到改善，并显著抑制了NF-κB信号级联、肥大标志基因的表达以及炎症和巨噬细胞基因的表达。以NF-κB为靶点的基因阵列分析显示，与Myo-TG小鼠相比，Myo-3M小鼠中的几个重要基因显著下调。此外，Myo-3M没有表现出任何凋亡基因的表达变化，表明显著抑制NF-κB的激活可以减少进一步的促炎反应，而不影响细胞对凋亡的易感性。因此，针对NF-κB的治疗策略的发展可能为预防心脏的不良病理生理后果提供一种有效的方法。
Nuclear factor-κB (NF-κB) is a ubiquitous transcription factor that regulates various kinds of genes including inflammatory molecules, macrophage infiltration factors, cell adhesion molecules, and so forth, in various disease processes including cardiac hypertrophy and heart failure. Previously, we have demonstrated that activation of NF-κB was required in myotrophin-induced cardiac hypertrophy, in spontaneously hypertensive rats, and in dilated cardiomyopathy human hearts. Moreover, our recent study using the myotrophin-overexpressed transgenic mouse (Myo-Tg) model showed that short hairpin RNA-mediated knockdown of NF-κB significantly attenuated cardiac mass associated with improved cardiac function. Although it has been shown that NF-κB is substantially involved in cardiovascular remodeling, it is not clear whether the continuous blockade of NF-κB is effective in cardiovascular remodeling. To address this question, we took a genetic approach using IκBα triple mutant mice (3M) bred with Myo-Tg mice (a progressive hypertrophy/heart failure model). The double transgenic mice (Myo-3M) displayed an attenuated cardiac hypertrophy (9.8±0.62 versus 5.4±0.34, p<0.001) and improved cardiac function associated with significant inhibition of the NF-κB signaling cascade, hypertrophy marker gene expression, and inflammatory and macrophage gene expression at 24 weeks of age compared to Myo-Tg mice. NF-κB-targeted gene array profiling displayed several important genes that were significantly downregulated in Myo-3M mice compared to Myo-Tg mice. Furthermore, Myo-3M did not show any changes of apoptotic gene expression, indicating that significant inhibition of NF-κB activation reduces further proinflammatory reactions without affecting susceptibility to apoptosis. Therefore, development of therapeutic strategies targeting NF-κB may provide an effective approach to prevent adverse cardiac pathophysiological consequences.