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

Ferreira JC, Boer BN, Grinberg M, Brum PC, Mochly-Rosen D - PLoS ONE (2012)

Bottom Line: Importantly, inhibition of PKCβII, using a selective PKCβII peptide inhibitor (βIIV5-3), improved proteasomal activity and conferred protection in cultured neonatal cardiomyocytes.We also show that sustained inhibition of PKCβII increased proteasomal activity, decreased accumulation of damaged and misfolded proteins and increased animal survival in two rat models of HF.Finally, increased cardiac PKCβII 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California, United States of America.

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 βII (PKCβII) in disrupting PQC. We show that active PKCβII directly phosphorylated the proteasome and inhibited proteasomal activity in vitro and in cultured neonatal cardiomyocytes. Importantly, inhibition of PKCβII, using a selective PKCβII peptide inhibitor (βIIV5-3), improved proteasomal activity and conferred protection in cultured neonatal cardiomyocytes. We also show that sustained inhibition of PKCβII increased proteasomal activity, decreased accumulation of damaged and misfolded proteins and increased animal survival in two rat models of HF. Interestingly, βIIV5-3-mediated protection was blunted by sustained proteasomal inhibition in HF. Finally, increased cardiac PKCβII 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 PKCβII as a novel inhibitor of proteasomal function. PQC disruption by increased PKCβII activity in vivo appears to contribute to the pathophysiology of heart failure, suggesting that PKCβII inhibition may benefit patients with heart failure. (218 words).

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Protein quality control re-establishment by PKCβII inhibition improves survival and cardiac integrity in myocardial infarction-induced model of heart failure.A. βIIV5-3 improved cardiac integrity in the post-MI-induced HF model in rats. Heart samples were collected from 22 week-old control (sham), TAT-treated and βIIV5-3-treated heart failure rats (10 wks after MI surgery). Samples from a non-infarcted area (contractile zone) were processed for electron microscopy analysis. The integrity of cardiac myofibril structure (arrow head) was analyzed in each group (n = 3 per group). N, nucleus; S, sarcomere; SR, sarcoplasmic reticulum; Z, Z disc; M, mitochondria. B. Schematic panel of sustained treatment with TAT, βIIV5-3, bortezomib or bortezomib plus βIIV5-3 in post-myocardial infarction-induced heart failure in rats. C. βIIV5-3 improved survival of rats with post-myocardial infarction-induced heart failure. Note that sustained treatment of heart failure rats with a specific proteasome inhibitor (bortezomib, 0,2 mg/kg, thrice weekly) either alone or combined with βIIV5-3 culminated in 100% mortality as well as abrogated the cardioprotective effects of βIIV5-3 treatment. Control (sham) rats treated with bortezomib did not present increased mortality. Error bars indicate SEM. *, p<0.05 compared to control (sham) rats. §, p<0.05 compared to βIIV5-3-treated heart failure rats. #, p<0.05 compared to TAT-treated heart failure rats.
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pone-0033175-g004: Protein quality control re-establishment by PKCβII inhibition improves survival and cardiac integrity in myocardial infarction-induced model of heart failure.A. βIIV5-3 improved cardiac integrity in the post-MI-induced HF model in rats. Heart samples were collected from 22 week-old control (sham), TAT-treated and βIIV5-3-treated heart failure rats (10 wks after MI surgery). Samples from a non-infarcted area (contractile zone) were processed for electron microscopy analysis. The integrity of cardiac myofibril structure (arrow head) was analyzed in each group (n = 3 per group). N, nucleus; S, sarcomere; SR, sarcoplasmic reticulum; Z, Z disc; M, mitochondria. B. Schematic panel of sustained treatment with TAT, βIIV5-3, bortezomib or bortezomib plus βIIV5-3 in post-myocardial infarction-induced heart failure in rats. C. βIIV5-3 improved survival of rats with post-myocardial infarction-induced heart failure. Note that sustained treatment of heart failure rats with a specific proteasome inhibitor (bortezomib, 0,2 mg/kg, thrice weekly) either alone or combined with βIIV5-3 culminated in 100% mortality as well as abrogated the cardioprotective effects of βIIV5-3 treatment. Control (sham) rats treated with bortezomib did not present increased mortality. Error bars indicate SEM. *, p<0.05 compared to control (sham) rats. §, p<0.05 compared to βIIV5-3-treated heart failure rats. #, p<0.05 compared to TAT-treated heart failure rats.

Mentions: Performed the experiments: JCBF. Wrote the paper: JCBF PCB DMR. Contributed to study design: JCBF. Collaborated on experiments shown in Figure 4: BNB MG. Collaborated on experiments shown in Figure 2: PCB. Directed and designed the study: DMR.


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

Ferreira JC, Boer BN, Grinberg M, Brum PC, Mochly-Rosen D - PLoS ONE (2012)

Protein quality control re-establishment by PKCβII inhibition improves survival and cardiac integrity in myocardial infarction-induced model of heart failure.A. βIIV5-3 improved cardiac integrity in the post-MI-induced HF model in rats. Heart samples were collected from 22 week-old control (sham), TAT-treated and βIIV5-3-treated heart failure rats (10 wks after MI surgery). Samples from a non-infarcted area (contractile zone) were processed for electron microscopy analysis. The integrity of cardiac myofibril structure (arrow head) was analyzed in each group (n = 3 per group). N, nucleus; S, sarcomere; SR, sarcoplasmic reticulum; Z, Z disc; M, mitochondria. B. Schematic panel of sustained treatment with TAT, βIIV5-3, bortezomib or bortezomib plus βIIV5-3 in post-myocardial infarction-induced heart failure in rats. C. βIIV5-3 improved survival of rats with post-myocardial infarction-induced heart failure. Note that sustained treatment of heart failure rats with a specific proteasome inhibitor (bortezomib, 0,2 mg/kg, thrice weekly) either alone or combined with βIIV5-3 culminated in 100% mortality as well as abrogated the cardioprotective effects of βIIV5-3 treatment. Control (sham) rats treated with bortezomib did not present increased mortality. Error bars indicate SEM. *, p<0.05 compared to control (sham) rats. §, p<0.05 compared to βIIV5-3-treated heart failure rats. #, p<0.05 compared to TAT-treated heart failure rats.
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Related In: Results  -  Collection

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pone-0033175-g004: Protein quality control re-establishment by PKCβII inhibition improves survival and cardiac integrity in myocardial infarction-induced model of heart failure.A. βIIV5-3 improved cardiac integrity in the post-MI-induced HF model in rats. Heart samples were collected from 22 week-old control (sham), TAT-treated and βIIV5-3-treated heart failure rats (10 wks after MI surgery). Samples from a non-infarcted area (contractile zone) were processed for electron microscopy analysis. The integrity of cardiac myofibril structure (arrow head) was analyzed in each group (n = 3 per group). N, nucleus; S, sarcomere; SR, sarcoplasmic reticulum; Z, Z disc; M, mitochondria. B. Schematic panel of sustained treatment with TAT, βIIV5-3, bortezomib or bortezomib plus βIIV5-3 in post-myocardial infarction-induced heart failure in rats. C. βIIV5-3 improved survival of rats with post-myocardial infarction-induced heart failure. Note that sustained treatment of heart failure rats with a specific proteasome inhibitor (bortezomib, 0,2 mg/kg, thrice weekly) either alone or combined with βIIV5-3 culminated in 100% mortality as well as abrogated the cardioprotective effects of βIIV5-3 treatment. Control (sham) rats treated with bortezomib did not present increased mortality. Error bars indicate SEM. *, p<0.05 compared to control (sham) rats. §, p<0.05 compared to βIIV5-3-treated heart failure rats. #, p<0.05 compared to TAT-treated heart failure rats.
Mentions: Performed the experiments: JCBF. Wrote the paper: JCBF PCB DMR. Contributed to study design: JCBF. Collaborated on experiments shown in Figure 4: BNB MG. Collaborated on experiments shown in Figure 2: PCB. Directed and designed the study: DMR.

Bottom Line: Importantly, inhibition of PKCβII, using a selective PKCβII peptide inhibitor (βIIV5-3), improved proteasomal activity and conferred protection in cultured neonatal cardiomyocytes.We also show that sustained inhibition of PKCβII increased proteasomal activity, decreased accumulation of damaged and misfolded proteins and increased animal survival in two rat models of HF.Finally, increased cardiac PKCβII 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California, United States of America.

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 βII (PKCβII) in disrupting PQC. We show that active PKCβII directly phosphorylated the proteasome and inhibited proteasomal activity in vitro and in cultured neonatal cardiomyocytes. Importantly, inhibition of PKCβII, using a selective PKCβII peptide inhibitor (βIIV5-3), improved proteasomal activity and conferred protection in cultured neonatal cardiomyocytes. We also show that sustained inhibition of PKCβII increased proteasomal activity, decreased accumulation of damaged and misfolded proteins and increased animal survival in two rat models of HF. Interestingly, βIIV5-3-mediated protection was blunted by sustained proteasomal inhibition in HF. Finally, increased cardiac PKCβII 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 PKCβII as a novel inhibitor of proteasomal function. PQC disruption by increased PKCβII activity in vivo appears to contribute to the pathophysiology of heart failure, suggesting that PKCβII inhibition may benefit patients with heart failure. (218 words).

Show MeSH
Related in: MedlinePlus