Institute of Physiological Chemistry, University of Ulm, 89081 Ulm, Germany.
Proc Natl Acad Sci U S A. 2012 Jul 17;109(29):11794-9. doi: 10.1073/pnas.1116584109. Epub 2012 Jul 2.
Inflammation is a major factor in heart disease. IκB kinase (IKK) and its downstream target NF-κB are regulators of inflammation and are activated in cardiac disorders, but their precise contributions and targets are unclear. We analyzed IKK/NF-κB function in the heart by a gain-of-function approach, generating an inducible transgenic mouse model with cardiomyocyte-specific expression of constitutively active IKK2. In adult animals, IKK2 activation led to inflammatory dilated cardiomyopathy and heart failure. Transgenic hearts showed infiltration with CD11b(+) cells, fibrosis, fetal reprogramming, and atrophy of myocytes with strong constitutively active IKK2 expression. Upon transgene inactivation, the disease was reversible even at an advanced stage. IKK-induced cardiomyopathy was dependent on NF-κB activation, as in vivo expression of IκBα superrepressor, an inhibitor of NF-κB, prevented the development of disease. Gene expression and proteomic analyses revealed enhanced expression of inflammatory cytokines, and an IFN type I signature with activation of the IFN-stimulated gene 15 (ISG15) pathway. In that respect, IKK-induced cardiomyopathy resembled Coxsackievirus-induced myocarditis, during which the NF-κB and ISG15 pathways were also activated. Vice versa, in cardiomyocytes lacking the regulatory subunit of IKK (IKKγ/NEMO), the induction of ISG15 was attenuated. We conclude that IKK/NF-κB activation in cardiomyocytes is sufficient to cause cardiomyopathy and heart failure by inducing an excessive inflammatory response and myocyte atrophy.
炎症是心脏病的一个主要因素。IKK 激酶（IKK）及其下游靶标 NF-κB 是炎症的调节剂，在心臟疾病中被激活，但它们的确切作用和靶点尚不清楚。我们通过功能获得方法分析了 IKK/NF-κB 在心脏中的作用，生成了一种具有心肌细胞特异性组成性激活 IKK2 表达的可诱导转基因小鼠模型。在成年动物中，IKK2 的激活导致炎症性扩张型心肌病和心力衰竭。转基因心脏表现出 CD11b（+）细胞浸润、纤维化、胎儿重编程以及具有强组成性激活 IKK2 表达的肌细胞萎缩。在转基因失活时，即使在晚期阶段，疾病也是可逆的。IKK 诱导的心肌病依赖于 NF-κB 的激活，因为体内表达 NF-κB 的抑制剂 IκBα 超阻遏物可防止疾病的发展。基因表达和蛋白质组学分析显示炎症细胞因子的表达增强，以及 IFN Ⅰ型签名，其中 IFN 刺激基因 15（ISG15）途径被激活。在这方面，IKK 诱导的心肌病类似于柯萨奇病毒诱导的心肌炎，在此期间 NF-κB 和 ISG15 途径也被激活。相反，在缺乏 IKK 调节亚基（IKKγ/NEMO）的心肌细胞中，ISG15 的诱导被减弱。我们的结论是，心肌细胞中 IKK/NF-κB 的激活足以通过诱导过度的炎症反应和肌细胞萎缩来引起心肌病和心力衰竭。
