Activation of Both the Calpain and Ubiquitin-Proteasome Systems Contributes to Septic Cardiomyopathy through Dystrophin Loss/Disruption and mTOR Inhibition

Autor(es)

Silva Freitas, Ana Caroline ; Figueiredo, Maria Jose ; Campos, Erica Carolina ; Soave, Danilo Figueiredo ; Ramos, Simone Gusmao ; Tanowitz, Herbert B. ; Celes, Mara Rubia N.

• Tipo de documento: Artigo Científico
• Fonte: PLoS One; v. 11, n. 11 NOV 23 2016.
• Citações Web of Science: 4

Resumo

Cardiac dysfunction caused by the impairment of myocardial contractility has been recognized as an important factor contributing to the high mortality in sepsis. Calpain activation in the heart takes place in response to increased intracellular calcium influx resulting in proteolysis of structural and contractile proteins with subsequent myocardial dysfunction. The purpose of the present study was to test the hypothesis that increased levels of calpain in the septic heart leads to disruption of structural and contractile proteins and that administration of calpain inhibitor-1 (N-acetyl-leucinyl-leucinyl-norleucinal (ALLN)) after sepsis induced by cecal ligation and puncture prevents cardiac protein degradation. We also tested the hypothesis that calpain plays a role in the modulation of protein synthesis/degradation through the activation of proteasome-dependent proteolysis and inhibition of the mTOR pathway. Severe sepsis significantly increased heart calpain-1 levels and promoted ubiquitin and Pa28 beta over-expression with a reduction in the mTOR levels. In addition, sepsis reduced the expression of structural proteins dystrophin and beta-dystroglycan as well as the contractile proteins actin and myosin. ALLN administration prevented sepsis-induced increases in calpain and ubiquitin levels in the heart, which resulted in decreased of structural and contractile proteins degradation and basal mTOR expression levels were re-established. Our results support the concept that increased calpain concentrations may be part of an important mechanism of sepsis-induced cardiac muscle proteolysis. (AU)

• Processo FAPESP: 12/23649-0 - Cardiomiopatia séptica como componente da síndrome de falência de múltiplos órgãos na sépsis grave
• Beneficiário: Simone Gusmão Ramos
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 07/58843-2 - O possivel papel do calcio no mecanismo intrinseco de perda primaria de distrofina na patogenese da disfuncao cardiaca na sepsis experimental.
• Beneficiário: Mara Rúbia Nunes Celes
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 12/17542-8 - O papel da via de sinalização fosfatidilinositol-3-quinase/serina-treonina quinase (PI3K/Akt) na expressão de distrofina no miocárdio de animais submetidos ao estímulo séptico por ligadura e perfuração do ceco (CLP)
• Beneficiário: Simone Gusmão Ramos
• Modalidade de apoio: Auxílio à Pesquisa - Regular