Protein Quality Control Disruption by PKC beta II in Heart Failure; Rescue by the Selective PKC beta II Inhibitor, beta IIV5-3

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art_BOER_Protein_Quality_Control_Disruption_by_PKC_beta_II_2012.PDF (903.59 KB)
Citações na Scopus
41
Tipo de produção
article
Data de publicação
2012
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PUBLIC LIBRARY SCIENCE
DOI
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Scopus
Web of Science
PubMed
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Autores
FERREIRA, Julio C. B.
BRUM, Patricia Chakur
MOCHLY-ROSEN, Daria
Autor de Grupo de pesquisa
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Citação
PLOS ONE, v.7, n.3, article ID e33175, 11p, 2012
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
Myocardial remodeling and heart failure (HF) are common sequelae of many forms of cardiovascular disease and a leading cause of mortality worldwide. Accumulation of damaged cardiac proteins in heart failure has been described. However, how protein quality control (PQC) is regulated and its contribution to HF development are not known. Here, we describe a novel role for activated protein kinase C isoform beta II (PKC beta II) in disrupting PQC. We show that active PKC beta II directly phosphorylated the proteasome and inhibited proteasomal activity in vitro and in cultured neonatal cardiomyocytes. Importantly, inhibition of PKC beta II, using a selective PKC beta II peptide inhibitor (beta IIV5-3), improved proteasomal activity and conferred protection in cultured neonatal cardiomyocytes. We also show that sustained inhibition of PKC beta II increased proteasomal activity, decreased accumulation of damaged and misfolded proteins and increased animal survival in two rat models of HF. Interestingly, beta IIV5-3-mediated protection was blunted by sustained proteasomal inhibition in HF. Finally, increased cardiac PKC beta II activity and accumulation of misfolded proteins associated with decreased proteasomal function were found also in remodeled and failing human hearts, indicating a potential clinical relevance of our findings. Together, our data highlights PKC beta II as a novel inhibitor of proteasomal function. PQC disruption by increased PKC beta II activity in vivo appears to contribute to the pathophysiology of heart failure, suggesting that PKC beta II inhibition may benefit patients with heart failure. (218 words)
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https://observatorio.fm.usp.br/handle/OPI/1518
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Coleções
Artigos e Materiais de Revistas Científicas - HC/InCor