title: Protein quality control disruption by PKCβII in heart failure; rescue by the selective PKCβII inhibitor, βIIV5-3.
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 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).
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Julio C B
authors.initials: JC
authors.lastname: Ferreira
authors.forename: Berta Napchan
authors.initials: BN
authors.lastname: Boer
authors.forename: Max
authors.initials: M
authors.lastname: Grinberg
authors.forename: Patricia Chakur
authors.initials: PC
authors.lastname: Brum
authors.forename: Daria
authors.initials: D
authors.lastname: Mochly-Rosen
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000831:Animals, Newborn; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D006801:Humans; D006973:Hypertension / Q000150:complications; D015151:Immunoblotting; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000150:complications; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D064546:Protein Kinase C beta; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D020303:Rats, Inbred Dahl; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D009842:Oligopeptides; D047428:Protein Kinase Inhibitors; D011506:Proteins; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D046988:Proteasome Endopeptidase Complex