TY - JOUR
T1 - Tumor necrosis factor-α confers cardioprotection through ectopic expression of keratins K8 and K18
AU - Papathanasiou, Stamatis
AU - Rickelt, Steffen
AU - Soriano, Maria Eugenia
AU - Schips, Tobias G.
AU - Maier, Harald J.
AU - Davos, Constantinos H.
AU - Varela, Aimilia
AU - Kaklamanis, Loukas
AU - Mann, Douglas L.
AU - Capetanaki, Yassemi
N1 - Publisher Copyright:
© 2015 Nature America, Inc. All rights reserved.
PY - 2015/9/8
Y1 - 2015/9/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84941022388&partnerID=8YFLogxK
U2 - 10.1038/nm.3925
DO - 10.1038/nm.3925
M3 - Article
C2 - 26280121
AN - SCOPUS:84941022388
SN - 1078-8956
VL - 21
SP - 1076
EP - 1084
JO - Nature medicine
JF - Nature medicine
IS - 9
ER -