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

ABSTRACT: Tumor necrosis factor-? (TNF-?), 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-? also exerts cytoprotective effects in heart failure is not known. Here we provide evidence for a cardioprotective function of TNF-? in a genetic heart failure model, desmin-deficient mice. The cardioprotective effects of TNF-? are a consequence of nuclear factor-?B (NF-?B)-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-? expression is upregulated, K8/K18 were also ectopically expressed and localized primarily at IDs, which did not contain detectable amounts of desmin. Thus, TNF-?- and NF-?B-mediated formation of an alternative, stress-induced intermediate filament cytoskeleton has cardioprotective function in mice and potentially in humans.

SUBMITTER: Papathanasiou S 

PROVIDER: S-EPMC5419049 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature