Tumor necrosis factor-α confers cardioprotection through ectopic expression of keratins K8 and K18.
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.
Center of Basic Research, Biomedical Research Foundation, Academy of Athens, Athens, Greece.
Stamatis
S
Papathanasiou
Helmholtz Group for Cell Biology, German Cancer Research Center, Heidelberg, Germany.
Steffen
S
Rickelt
Department of Biology, University of Padova, Padova, Italy.
Maria Eugenia
ME
Soriano
Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Tobias G
TG
Schips
Institute of Physiological Chemistry, University of Ulm, Ulm, Germany.
Harald J
HJ
Maier
Clinical, Experimental Surgery &Translational Research Center, Biomedical Research Foundation, Academy of Athens, Athens, Greece.
Constantinos H
CH
Davos
Clinical, Experimental Surgery &Translational Research Center, Biomedical Research Foundation, Academy of Athens, Athens, Greece.
Aimilia
A
Varela
Department of Pathology, Onassis Cardiac Surgery Center, Athens, Greece.
Loukas
L
Kaklamanis
Center for Cardiovascular Research, Division of Cardiology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri, USA.
Douglas L
DL
Mann
Center of Basic Research, Biomedical Research Foundation, Academy of Athens, Athens, Greece.
Yassemi
Y
Capetanaki
D000818:Animals; D006332:Cardiomegaly / Q000517:prevention & control; D003893:Desmin / Q000502:physiology; D005260:Female; D006801:Humans; D053538:Keratin-18 / Q000502:physiology*; D053533:Keratin-8 / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D003893:Desmin; D053538:Keratin-18; D053533:Keratin-8; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha