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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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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Ferreira, Julio C. B. [1, 2] ; Boer, Berta Napchan [3] ; Grinberg, Max [3] ; Brum, Patricia Chakur [2] ; Mochly-Rosen, Daria [1]
Total Authors: 5
[1] Stanford Univ, Sch Med, Dept Chem & Syst Biol, Stanford, CA 94305 - USA
[2] Univ Sao Paulo, Sch Phys Educ & Sport, Sao Paulo - Brazil
[3] Univ Sao Paulo, Sch Med, Heart Inst InCor, Sao Paulo - Brazil
Total Affiliations: 3
Document type: Journal article
Source: PLoS One; v. 7, n. 3 MAR 30 2012.
Web of Science Citations: 31

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) (AU)

FAPESP's process: 09/03143-1 - Protein quality control in heart failure: role of different protein kinase C isozymes
Grantee:Julio Cesar Batista Ferreira
Support type: Scholarships in Brazil - Post-Doctorate