Cleavage of IκBα by calpain induces myocardial NF-κB activation, TNF-α expression, and cardiac dysfunction in septic mice.
Am J Physiol Heart Circ Physiol
; 306(6): H833-43, 2014 Mar.
Article
em En
| MEDLINE
| ID: mdl-24441549
ABSTRACT
Recent studies in septic models have shown that myocardial calpain activity and TNF-α expression increase during sepsis and that inhibition of calpain activation downregulates myocardial TNF-α expression and improves cardiac dysfunction. However, the mechanism underlying this pathological process is unclear. Thus, in the present study, we aimed to explore whether IκBα/NF-κB signaling linked myocardial calpain activity and TNF-α expression in septic mice. Adult male mice were injected with LPS (4 mg/kg ip) to induce sepsis. Myocardial calpain activity, IκBα/NF-κB signaling activity, and TNF-α expression were assessed, and myocardial function was evaluated using the Langendorff system. In septic mice, myocardial calpain activity and TNF-α expression were increased and IκBα protein was degraded. Furthermore, NF-κB was activated, as indicated by increased NF-κB p65 phosphorylation, cleavage of p105 into p50, and its nuclear translocation. Administration of the calpain inhibitors calpain inhibitor Ш and PD-150606 prevented the LPS-induced degradation of myocardial IκBα, NF-κB activation, and TNF-α expression and ultimately improved myocardial function. In calpastatin transgenic mice, an endogenous calpain inhibitor and cultured neonatal mouse cardiomyocytes overexpressing calpastatin also inhibited calpain activity, IκBα protein degradation, and NF-κB activation after LPS treatment. In conclusion, myocardial calpain activity was increased in septic mice. Calpain induced myocardial NF-κB activation, TNF-α expression, and myocardial dysfunction in septic mice through IκBα protein cleavage.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Calpaína
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NF-kappa B
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Fator de Necrose Tumoral alfa
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Sepse
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Proteínas I-kappa B
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Cardiopatias
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Miocárdio
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article