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Nat Med. 2015 Sep;21(9):1076-84. doi: 10.1038/nm.3925. Epub 2015 Aug 17.

Tumor necrosis factor-α confers cardioprotection through ectopic expression of keratins K8 and K18.

Author information

1
Center of Basic Research, Biomedical Research Foundation, Academy of Athens, Athens, Greece.
2
Helmholtz Group for Cell Biology, German Cancer Research Center, Heidelberg, Germany.
3
Department of Biology, University of Padova, Padova, Italy.
4
Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
5
Institute of Physiological Chemistry, University of Ulm, Ulm, Germany.
6
Clinical, Experimental Surgery &Translational Research Center, Biomedical Research Foundation, Academy of Athens, Athens, Greece.
7
Department of Pathology, Onassis Cardiac Surgery Center, Athens, Greece.
8
Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri, USA.

Abstract

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.

PMID:
26280121
PMCID:
PMC5419049
DOI:
10.1038/nm.3925
[Indexed for MEDLINE]
Free PMC Article

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