| First Author | Papathanasiou S | Year | 2015 |
| Journal | Nat Med | Volume | 21 |
| Issue | 9 | Pages | 1076-84 |
| PubMed ID | 26280121 | Mgi Jnum | J:329733 |
| Mgi Id | MGI:6838728 | Doi | 10.1038/nm.3925 |
| Citation | Papathanasiou S, et al. (2015) Tumor necrosis factor-alpha confers cardioprotection through ectopic expression of keratins K8 and K18. Nat Med 21(9):1076-84 |
| abstractText | Tumor necrosis factor-alpha (TNF-alpha), 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-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-kappaB (NF-kappaB)-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-alpha expression is upregulated, K8/K18 were also ectopically expressed and localized primarily at IDs, which did not contain detectable amounts of desmin. Thus, TNF-alpha- and NF-kappaB-mediated formation of an alternative, stress-induced intermediate filament cytoskeleton has cardioprotective function in mice and potentially in humans. |
