Proteasome proteolytic activities were markedly reduced in failing and hypertrophic cardiomyopathy hearts compared with nonfailing donor hearts (P<0.01).
Observational
p-value: p=<0.01
BACKGROUND: The ubiquitin proteasome system maintains a dynamic equilibrium of proteins and prevents accumulation of damaged and misfolded proteins, yet its role in human cardiac dysfunction is not well understood. The present study evaluated ubiquitin proteasome system function in human heart failure and hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: Proteasome function was studied in human nonfailing donor hearts, explanted failing hearts, and myectomy samples from patients with HCM. Proteasome proteolytic activities were markedly reduced in failing and HCM hearts compared with nonfailing hearts (P<0.01). This activity was partially restored after mechanical unloading in failing hearts (P<0.01) and was significantly lower in HCM hearts with pathogenic sarcomere mutations than in those lacking these mutations (P<0.05). There were no changes in the protein content of ubiquitin proteasome system subunits (ie, 11S, 20S, and 19S) or in active-site labeling of the 20S proteolytic subunit beta-5 among groups to explain decreased ubiquitin proteasome system activity in HCM and failing hearts. Examination of protein oxidation revealed that total protein carbonyls, 4-hydroxynonenylated proteins, and oxidative modification to 19S ATPase subunit Rpt 5 were increased in failing compared with nonfailing hearts. CONCLUSIONS: Proteasome activity in HCM and failing human hearts is impaired in the absence of changes in proteasome protein content or availability of proteolytic active sites. These data provide strong evidence that posttranslational modifications to the proteasome may account for defective protein degradation in human cardiomyopathies.
Predmore et al. (2010) conducted an observational in Heart failure and hypertrophic cardiomyopathy. Heart failure and hypertrophic cardiomyopathy vs. Nonfailing donor hearts was evaluated on Proteasome proteolytic activities (p=<0.01). Proteasome proteolytic activities were markedly reduced in failing and hypertrophic cardiomyopathy hearts compared with nonfailing donor hearts (P<0.01).