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Protein quality control disruption by PKCbetaII in heart failure
Author(s) -
Ferreira Julio C.B.,
Mochly-Rosen Daria,
Brum Patricia Chakur
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1054.12
Subject(s) - heart failure , proteasome , cardiomyopathy , medicine , myocardial infarction , dilated cardiomyopathy , in vitro , endocrinology , chemistry , biology , microbiology and biotechnology , biochemistry
Some genetic forms of human cardiomyopathy result from accumulation of damaged proteins. However, it is not known whether damaged proteins contribute to other forms of cardiomyopathies and heart failure (HF). We found that failing human hearts from two different etiologies displayed three fold increases in misfolded proteins, an ~50% decrease in proteasomal activity (the machinery that disposes of them) and an ~5 fold increase in levels and ~2.5 fold increased activity in cardiac protein kinase C betaII (PKCbetaII) relative to control hearts. Myocardial infarction‐induced and hypertension‐induced heart failure models in rats also exhibited a 50% reduction in cardiac proteasomal activity, an ~3 fold increase in damaged and misfolded proteins, as well as an ~3 fold increased PKCbetaII activity. PKCbetaII directly phosphorylated the proteasome and inhibited its activity, in vitro. Finally, we showed that sustained and selective PKCbetaII inhibition with betaIIV5‐3 (but not the selective inhibition of PKCbetaI, delta or epsilon) re‐established cardiac protein quality control and reversed HF in both models. Therefore, accumulation of abnormal proteins, disruption of protein quality control and increased activity of PKCbetaII appear to contribute to the pathophysiology of heart failure, suggesting that PKCbetaII inhibition may benefit patients with heart failure.