Dataset Information

Protein quality control disruption by PKC?II in heart failure; rescue by the selective PKC?II inhibitor, ?IIV5-3.

ABSTRACT: 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 ?II (PKC?II) in disrupting PQC. We show that active PKC?II directly phosphorylated the proteasome and inhibited proteasomal activity in vitro and in cultured neonatal cardiomyocytes. Importantly, inhibition of PKC?II, using a selective PKC?II peptide inhibitor (?IIV5-3), improved proteasomal activity and conferred protection in cultured neonatal cardiomyocytes. We also show that sustained inhibition of PKC?II increased proteasomal activity, decreased accumulation of damaged and misfolded proteins and increased animal survival in two rat models of HF. Interestingly, ?IIV5-3-mediated protection was blunted by sustained proteasomal inhibition in HF. Finally, increased cardiac PKC?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?II as a novel inhibitor of proteasomal function. PQC disruption by increased PKC?II activity in vivo appears to contribute to the pathophysiology of heart failure, suggesting that PKC?II inhibition may benefit patients with heart failure. (218 words).

SUBMITTER: Ferreira JC

PROVIDER: S-EPMC3316563 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Protein quality control disruption by PKCβII in heart failure; rescue by the selective PKCβII inhibitor, βIIV5-3.

Ferreira Julio C B JC Boer Berta Napchan BN Grinberg Max M Brum Patricia Chakur PC Mochly-Rosen Daria D

PloS one 20120330 3

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 βII (PKCβII) in disrupting PQC. We show that active PKCβII directly phosphorylated the protea ...[more]

PMID: 22479367

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Project description:Previous studies in patients with atrial fibrillation showed that a history of heart failure (HF) could negatively impact anticoagulation quality, as measured by the average time in therapeutic range (TTR). Whether additional markers of HF severity are associated with TTR has not been investigated thoroughly. We aimed to examine the potential role of HF severity in the quality of warfarin control in patients with HF with reduced ejection fraction. Data from the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction Trial were used to investigate the association between TTR and HF severity. Multivariable logistic regression models were used to examine the association of markers of HF severity, including New York Heart Association (NYHA) class, Minnesota Living with HF (MLWHF) score, and frequency of HF hospitalization, with TTR ≥70% (high TTR). We included 1,067 participants (high TTR, N = 413; low TTR, N = 654) in the analysis. In unadjusted analysis, patients with a high TTR were older and less likely to have had strokes or receive other antiplatelet agents. Those patients also had lower NYHA class, better MLWHF scores, greater 6-minute walk distance, and lower frequency of HF hospitalizations. Multivariable analysis showed that NYHA class III and/or IV (Odds ratio [OR] 0.68 [95% confidence intervals [CIs] 0.49 to 0.94]), each 10-point increase in MLWHF score (i.e., worse health-related quality of life) (OR 0.92 [0.86 to 0.99]), and higher number of HF hospitalization per year (OR0.45 [0.30 to 0.67]) were associated with decreased likelihood of having high TTR. In HF patients with systolic dysfunction, NYHA class III and/or IV, poor health-related quality of life, and a higher rate of HF hospitalization were independently associated with suboptimal quality of warfarin anticoagulation control. These results affirm the need to assess the new approaches, such as direct oral anticoagulants, to prevent thromboembolism in this patient population.

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Dataset Information

Protein quality control disruption by PKC?II in heart failure; rescue by the selective PKC?II inhibitor, ?IIV5-3.

Publications

Protein quality control disruption by PKCβII in heart failure; rescue by the selective PKCβII inhibitor, βIIV5-3.

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