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

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 a...

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Autores principales: Freitas, Ana Caroline Silva, Figueiredo, Maria Jose, Campos, Erica Carolina, Soave, Danilo Figueiredo, Ramos, Simone Gusmao, Tanowitz, Herbert B., Celes, Mara Rúbia N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120800/
https://www.ncbi.nlm.nih.gov/pubmed/27880847
http://dx.doi.org/10.1371/journal.pone.0166839
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author Freitas, Ana Caroline Silva
Figueiredo, Maria Jose
Campos, Erica Carolina
Soave, Danilo Figueiredo
Ramos, Simone Gusmao
Tanowitz, Herbert B.
Celes, Mara Rúbia N.
author_facet Freitas, Ana Caroline Silva
Figueiredo, Maria Jose
Campos, Erica Carolina
Soave, Danilo Figueiredo
Ramos, Simone Gusmao
Tanowitz, Herbert B.
Celes, Mara Rúbia N.
author_sort Freitas, Ana Caroline Silva
collection PubMed
description 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 Pa28β over-expression with a reduction in the mTOR levels. In addition, sepsis reduced the expression of structural proteins dystrophin and β-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.
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spelling pubmed-51208002016-12-15 Activation of Both the Calpain and Ubiquitin-Proteasome Systems Contributes to Septic Cardiomyopathy through Dystrophin Loss/Disruption and mTOR Inhibition Freitas, Ana Caroline Silva Figueiredo, Maria Jose Campos, Erica Carolina Soave, Danilo Figueiredo Ramos, Simone Gusmao Tanowitz, Herbert B. Celes, Mara Rúbia N. PLoS One Research Article 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 Pa28β over-expression with a reduction in the mTOR levels. In addition, sepsis reduced the expression of structural proteins dystrophin and β-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. Public Library of Science 2016-11-23 /pmc/articles/PMC5120800/ /pubmed/27880847 http://dx.doi.org/10.1371/journal.pone.0166839 Text en © 2016 Freitas et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Freitas, Ana Caroline Silva
Figueiredo, Maria Jose
Campos, Erica Carolina
Soave, Danilo Figueiredo
Ramos, Simone Gusmao
Tanowitz, Herbert B.
Celes, Mara Rúbia N.
Activation of Both the Calpain and Ubiquitin-Proteasome Systems Contributes to Septic Cardiomyopathy through Dystrophin Loss/Disruption and mTOR Inhibition
title Activation of Both the Calpain and Ubiquitin-Proteasome Systems Contributes to Septic Cardiomyopathy through Dystrophin Loss/Disruption and mTOR Inhibition
title_full Activation of Both the Calpain and Ubiquitin-Proteasome Systems Contributes to Septic Cardiomyopathy through Dystrophin Loss/Disruption and mTOR Inhibition
title_fullStr Activation of Both the Calpain and Ubiquitin-Proteasome Systems Contributes to Septic Cardiomyopathy through Dystrophin Loss/Disruption and mTOR Inhibition
title_full_unstemmed Activation of Both the Calpain and Ubiquitin-Proteasome Systems Contributes to Septic Cardiomyopathy through Dystrophin Loss/Disruption and mTOR Inhibition
title_short Activation of Both the Calpain and Ubiquitin-Proteasome Systems Contributes to Septic Cardiomyopathy through Dystrophin Loss/Disruption and mTOR Inhibition
title_sort activation of both the calpain and ubiquitin-proteasome systems contributes to septic cardiomyopathy through dystrophin loss/disruption and mtor inhibition
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120800/
https://www.ncbi.nlm.nih.gov/pubmed/27880847
http://dx.doi.org/10.1371/journal.pone.0166839
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