A novel mechanism of cardioprotection through TNF-α-induced ectopic expression of keratins K8 and K18

摘要

The adult myocardium demonstrates a unique system of adaptation upon stress stimuli, in an effort to maintain its overall homeostasis. This compensatory mechanism remains a mystery. Tumor Necrosis Factor-α (TNF-α) is one of the major stress-induced pro-inflammatory cytokines that is up-regulated in heart failure^, and its sustained expression is considered detrimental for the heart^,–. Although previous studies have shown that lower levels of TNF-α confer cytoprotection in the myocardium following ischemic reperfusion injury, such action in heart failure remains elusive. Here we propose a novel cardioprotective function for TNF-α overexpression in a genetic heart failure model, the desmin deficient mice, through NF-κB-mediated cardiomyocyte ectopic expression of keratin 8 (K8) and keratin 18 (K18), two simple epithelia-specific Intermediate Filament (IF) proteins. The ectopically expressed K8 and K18 (K8/K18) form a cytoskeletal network that localizes mainly at the Intercalated Discs (IDs). This alternative K8/K18 cytoskeleton confers cardioprotection by a mechanism that maintains ID and mitochondrial integrity and function. Importantly, we demonstrated that K8/K18 ectopic induction takes place in other genetic and experimental models of heart failure and showed a cardioprotective function in mice subjected to transverse aortic constriction. Finally, we discovered that in cardiomyocytes of human failing myocardium, where TNF-α is induced, K8/K18 are also ectopically expressed and localize primarily at IDs, where desmin cannot be detected. This is the first report to propose a TNFα-mediated cardiac ectopic expression of K8/K18 IF proteins, which may act as stress-induced cardioprotective factors in the failing heart, a phenomenon of major clinical significance as it also extends to human heart failure.