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Tipo do documento: Artigo
Título: Disruption of calcium homeostasis in cardiomyocytes underlies cardiac structural and functional changes in severe sepsis
Autor: Celes, Mara Rúbia Nunes
Malvestio, Lygia Maria Mouri
Suadicani, Sylvia O.
Prado, Cibele Maria
Figueiredo, Maria José
Pulici, Érica Carolina Campos
Freitas, Ana Caroline Silva de
Spray, David C.
Tanowitz, Herbert B.
Santos, José Sebastião dos
Rossi, Marcos Antonio
Abstract: Sepsis, a major cause of morbidity/mortality in intensive care units worldwide, is commonly associated with cardiac dysfunction, which worsens the prognosis dramatically for patients. Although in recent years the concept of septic cardiomyopathy has evolved, the importance of myocardial structural alterations in sepsis has not been fully explored. This study offers novel and mechanistic data to clarify subcellular events that occur in the pathogenesis of septic cardiomyopathy and myocardial dysfunction in severe sepsis. Cultured neonatal mice cardiomyocytes subjected to serum obtained from mice with severe sepsis presented striking increment of [Ca2+]i and calpain-1 levels associated with decreased expression of dystrophin and disruption and derangement of F-actin filaments and cytoplasmic bleb formation. Severe sepsis induced in mice led to an increased expression of calpain-1 in cardiomyocytes. Moreover, decreased myocardial amounts of dystrophin, sarcomeric actin, and myosin heavy chain were observed in septic hearts associated with depressed cardiac contractile dysfunction and a very low survival rate. Actin and myosin from the sarcomere are first disassembled by calpain and then ubiquitinated and degraded by proteasome or sequestered inside specialized vacuoles called autophagosomes, delivered to the lysosome for degradation forming autophagolysosomes. Verapamil and dantrolene prevented the increase of calpain-1 levels and preserved dystrophin, actin, and myosin loss/reduction as well cardiac contractile dysfunction associated with strikingly improved survival rate. These abnormal parameters emerge as therapeutic targets, which modulation may provide beneficial effects on future vascular outcomes and mortality in sepsis. Further studies are needed to shed light on this mechanism, mainly regarding specific calpain inhibitors.
País: Estados unidos
Unidade acadêmica: Instituto de Patologia Tropical e Saúde Pública - IPTSP (RG)
Citação: CELES, Mara R. N.; MALVESTIO, Lygia M.; SUADICANI, Sylvia O.; PRADO, Cibele M.; FIGUEIREDO, Maria J.; CAMPOS, Erica C.; FREITAS, Ana C. S.; SPRAY, David C.; TANOWITZ, Herbert B.; SILVA, João S. da; ROSSI, Marcos A. Disruption of calcium homeostasis in cardiomyocytes underlies cardiac structural and functional changes in severe sepsis. Plos One, San Francisco, v. 8, n. 7, e68809, 2013.
Tipo de acesso: Acesso Aberto
Identificador do documento: 10.1371/journal.pone.0068809
Identificador do documento: 10.1371/journal.pone.0068809
Data de publicação: 23-Jul-2013
Aparece nas coleções:IPTSP - Artigos publicados em periódicos

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