%0 Journal Article
%A Papathanasiou, Stamatis
%A Rickelt, Steffen
%A Soriano, Maria Eugenia
%A Schips, Tobias G
%A Maier, Harald J
%A Davos, Constantinos H
%A Varela, Aimilia
%A Kaklamanis, Loukas
%A Mann, Douglas L
%A Capetanaki, Yassemi
%T Tumor necrosis factor-α confers cardioprotection through ectopic expression of keratins K8 and K18.
%J Nature medicine
%V 21
%N 9
%@ 1546-170X
%C New York, NY
%I Nature America Inc.
%M DKFZ-2017-03295
%P 1076 - 1084
%D 2015
%X Tumor necrosis factor-α (TNF-α), one of the major stress-induced proinflammatory cytokines, is upregulated in the heart after tissue injury, and its sustained expression can contribute to the development of heart failure. Whether TNF-α also exerts cytoprotective effects in heart failure is not known. Here we provide evidence for a cardioprotective function of TNF-α in a genetic heart failure model, desmin-deficient mice. The cardioprotective effects of TNF-α are a consequence of nuclear factor-κB (NF-κB)-mediated ectopic expression in cardiomyocytes of keratin 8 (K8) and keratin 18 (K18), two epithelial-specific intermediate filament proteins. 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-α expression is upregulated, K8/K18 were also ectopically expressed and localized primarily at IDs, which did not contain detectable amounts of desmin. Thus, TNF-α- and NF-κB-mediated formation of an alternative, stress-induced intermediate filament cytoskeleton has cardioprotective function in mice and potentially in humans.
%K Desmin (NLM Chemicals)
%K Keratin-18 (NLM Chemicals)
%K Keratin-8 (NLM Chemicals)
%K NF-kappa B (NLM Chemicals)
%K Tumor Necrosis Factor-alpha (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:26280121
%2 pmc:PMC5419049
%R 10.1038/nm.3925
%U https://inrepo02.dkfz.de/record/127270