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Disruption of sarcolemmal dystrophin and beta-dystroglycan may be a potential mechanism for myocardial dysfunction in severe sepsis

Texto completo
Autor(es):
Celes, Mara Rubia N. [1] ; Torres-Duenas, Diego [2] ; Malvestio, Lygia M. [1] ; Blefari, Valdecir [1] ; Campos, Erica C. [1] ; Ramos, Simone G. [1] ; Prado, Cibele M. [1] ; Cunha, Fernando Q. [2] ; Rossi, Marcos A. [1]
Número total de Autores: 9
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Pathol, Lab Cellular & Mol Cardiol, BR-14049900 Sao Paulo - Brazil
[2] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Pharmacol, Lab Immunopharmacol, BR-14049900 Sao Paulo - Brazil
Número total de Afiliações: 2
Tipo de documento: Artigo Científico
Fonte: LABORATORY INVESTIGATION; v. 90, n. 4, p. 531-542, APR 2010.
Citações Web of Science: 15
Resumo

Evidence from our laboratory has shown alterations in myocardial structure in severe sepsis/septic shock. The morphological alterations are heralded by sarcolemmal damage, characterized by increased plasma membrane permeability caused by oxidative damage to lipids and proteins. The critical importance of the dystrophin-glycoprotein complex (DGC) in maintaining sarcolemmal stability led us to hypothesize that loss of dystrophin and associated glycoproteins could be involved in early increased sarcolemmal permeability in experimentally induced septic cardiomyopathy. Male C57Bl/6 mice were subjected to sham operation and moderate (MSI) or severe (SSI) septic injury induced by cecal ligation and puncture (CLP). Using western blot and immunofluorescence, a downregulation of dystrophin and beta-dystroglycan expression in both severe and moderate injury could be observed in septic hearts. The immunofluorescent and protein amount expressions of laminin-alpha 2 were similar in SSI and sham-operated hearts. Consonantly, the evaluation of plasma membrane permeability by intracellular albumin staining provided evidence of severe injury of the sarcolemma in SSI hearts, whereas antioxidant treatment significantly attenuated the loss of sarcolemmal dystrophin expression and the increased membrane permeability. This study offers novel and mechanistic data to clarify subcellular events in the pathogenesis of cardiac dysfunction in severe sepsis. The main finding was that severe sepsis leads to a marked reduction in membrane localization of dystrophin and beta-dystroglycan in septic cardiomyocytes, a process that may constitute a structural basis of sepsis-induced cardiac depression. In addition, increased sarcolemmal permeability suggests functional impairment of the DGC complex in cardiac myofibers. In vivo observation that antioxidant treatment significantly abrogated the loss of dystrophin expression and plasma membrane increased permeability supports the hypothesis that oxidative damage may mediate the loss of dystrophin and beta-dystroglycan in septic mice. These abnormal parameters emerge as therapeutic targets and their modulation may provide beneficial effects on future cardiovascular outcomes and mortality in sepsis. Laboratory Investigation (2010) 90, 531-542; doi: 10.1038/labinvest.2010.3; published online 8 February 2010 (AU)

Processo FAPESP: 07/58843-2 - O possível papel do cálcio no mecanismo intrínseco de perda primária de distrofina na patogênese da disfunção cardíaca na sépsis experimental
Beneficiário:Mara Rúbia Nunes Celes
Linha de fomento: Bolsas no Brasil - Pós-Doutorado
Processo FAPESP: 06/52882-3 - O possível papel do complexo de glicoproteínas associadas à distrofina na morte súbita na tripanosomíase americana experimental
Beneficiário:Cibele Maria Prado Zinni
Linha de fomento: Bolsas no Brasil - Pós-Doutorado
Processo FAPESP: 06/59618-0 - O possível papel do complexo de glicoproteínas associadas à distrofia na morte súbita na tripanossomiase americana experimental
Beneficiário:Marcos Antonio Rossi
Linha de fomento: Auxílio à Pesquisa - Regular
Processo FAPESP: 07/59448-0 - O possível papel do complexo distrofina-glicoproteínas associadas na cardiomiopatia dilatada experimental induzida pelo antineoplásico doxorrubicina
Beneficiário:Erica Carolina Campos Pulici
Linha de fomento: Bolsas no Brasil - Doutorado
Processo FAPESP: 07/52556-1 - Imunopatogênese da lesão periapical experimentalmente induzida em camundongos knockout de citocinas Th1 (IFNy) e Th2 (IL-4 and IL-10), molécula de adesão intercelular (ICAM-1) e receptor de quimiocina (CCR5): panorama geral de possíveis mecanismos envolvidos no estímulo ou proteção da reabsorção óssea
Beneficiário:Marcos Antonio Rossi
Linha de fomento: Auxílio à Pesquisa - Regular