Tumor necrosis factor-α confers cardioprotection through ectopic expression of keratins K8 and K18
Tumor necrosis factor-α confers cardioprotection through ectopic expression of keratins K8 and K18
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DOI：
10.1038/nm.3925
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发表时间：
2015-09-01
期刊：
影响因子：
82.9
通讯作者：
Capetanaki, Yassemi
中科院分区：
文献类型：
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作者：
Papathanasiou, Stamatis;Rickelt, Steffen;Capetanaki, Yassemi
肿瘤坏死因子-α（TNF-α）是一种主要的应激诱导的促炎细胞因子，在组织损伤后在心脏中上调（1，2），其持续表达可导致心力衰竭的发生（1，3，4）。TNF-α是否也在心力衰竭中发挥细胞保护作用尚不清楚。在这里，我们提供的证据表明，TNF-α在遗传性心力衰竭模型，结蛋白缺陷小鼠的心脏保护功能。TNF-α的心脏保护作用是核因子-κ B（NF-κ B）介导的角蛋白8（K8）和角蛋白18（K18）（两种上皮特异性中间丝蛋白）在心肌细胞中异位表达的结果（5，6）。在心肌细胞中，K8和K18（K8/K18）形成了一个替代的细胞骨架网络，主要位于闰盘（ID），并通过维持正常的ID结构和线粒体的完整性和功能来提供心脏保护。心肌细胞中K8/K18表达的异位诱导也发生在心力衰竭的其他遗传和实验模型中。K8/K18网络的丢失导致了横向主动脉缩窄后适应不良的心脏表型。在TNF-α表达上调的人衰竭心肌中（2），K8/K18也异位表达，并主要定位于ID，其中不含可检测量的结蛋白。因此，TNF-α-和NF-κ B介导的替代性应激诱导的中间丝细胞骨架的形成在小鼠和潜在的人类中具有心脏保护功能。
Tumor necrosis factor-alpha (TNF-alpha), one of the major stress-induced proinflammatory cytokines, is upregulated in the heart after tissue injury(1,2), and its sustained expression can contribute to the development of heart failure(1,3,4). Whether TNF-alpha also exerts cytoprotective effects in heart failure is not known. Here we provide evidence for a cardioprotective function of TNF-alpha in a genetic heart failure model, desmin-deficient mice. The cardioprotective effects of TNF-alpha are a consequence of nuclear factor-kappa B (NF-kappa B)-mediated ectopic expression in cardiomyocytes of keratin 8 (K8) and keratin 18 (K18), two epithelial-specific intermediate filament proteins(5,6). In cardiomyocytes, K8 and K18 (K8/K18) formed an alternative cytoskeletal network that localized mainly at intercalated discs (IDs) and conferred cardioprotection by maintaining normal ID structure and mitochondrial integrity and function. Ectopic induction of K8/K18 expression in cardiomyocytes also occurred in other genetic and experimental models of heart failure. Loss of the K8/K18 network resulted in a maladaptive cardiac phenotype following transverse aortic constriction. In human failing myocardium, where TNF-alpha expression is upregulated(2), K8/K18 were also ectopically expressed and localized primarily at IDs, which did not contain detectable amounts of desmin. Thus, TNF-alpha- and NF-kappa B-mediated formation of an alternative, stress-induced intermediate filament cytoskeleton has cardioprotective function in mice and potentially in humans.