Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Enhancement of proteasomal function protects against cardiac proteinopathy and ischemia/reperfusion injury in mice
Jie Li, … , Jeffrey Robbins, Xuejun Wang
Jie Li, … , Jeffrey Robbins, Xuejun Wang
Published August 15, 2011
Citation Information: J Clin Invest. 2011;121(9):3689-3700. https://doi.org/10.1172/JCI45709.
View: Text | PDF
Research Article Cardiology

Enhancement of proteasomal function protects against cardiac proteinopathy and ischemia/reperfusion injury in mice

  • Text
  • PDF
Abstract

The ubiquitin-proteasome system degrades most intracellular proteins, including misfolded proteins. Proteasome functional insufficiency (PFI) has been observed in proteinopathies, such as desmin-related cardiomyopathy, and implicated in many common diseases, including dilated cardiomyopathy and ischemic heart disease. However, the pathogenic role of PFI has not been established. Here we created inducible Tg mice with cardiomyocyte-restricted overexpression of proteasome 28 subunit α (CR-PA28αOE) to investigate whether upregulation of the 11S proteasome enhances the proteolytic function of the proteasome in mice and, if so, whether the enhancement can rescue a bona fide proteinopathy and protect against ischemia/reperfusion (I/R) injury. We found that CR-PA28αOE did not alter the homeostasis of normal proteins and cardiac function, but did facilitate the degradation of a surrogate misfolded protein in the heart. By breeding mice with CR-PA28αOE with mice representing a well-established model of desmin-related cardiomyopathy, we demonstrated that CR-PA28αOE markedly reduced aberrant protein aggregation. Cardiac hypertrophy was decreased, and the lifespan of the animals was increased. Furthermore, PA28α knockdown promoted, whereas PA28α overexpression attenuated, accumulation of the mutant protein associated with desmin-related cardiomyopathy in cultured cardiomyocytes. Moreover, CR-PA28αOE limited infarct size and prevented postreperfusion cardiac dysfunction in mice with myocardial I/R injury. We therefore conclude that benign enhancement of cardiac proteasome proteolytic function can be achieved by CR-PA28αOE and that PFI plays a major pathogenic role in cardiac proteinopathy and myocardial I/R injury.

Authors

Jie Li, Kathleen M. Horak, Huabo Su, Atsushi Sanbe, Jeffrey Robbins, Xuejun Wang

×

Figure 1

PA28α and PA28β expression in hearts of mice with CR-PA28αOE.

Options: View larger image (or click on image) Download as PowerPoint
PA28α and PA28β expression in hearts of mice with CR-PA28αOE.
(A) 3 Tg r...
(A) 3 Tg responder lines carrying Tg PA28α were crossbred with the tTA Tg mice. No Dox was given to the breeding pairs or pups. Western blot analyses of 2-month-old mouse heart samples show that CR-PA28αOE resulted in a proportional increase of PA28β protein in the PA28α/tTA double-Tg mice. (B) Quantitative densitometry analyses of PA28α and PA28β protein levels. n = 3, *P < 0.001 vs. non-Tg (NTG); #P < 0.001 vs. tTA single-Tg. (C and D) Representative Northern blot analyses for PA28α (C) and PA28β (D). (E) Quantitative analysis of PA28β mRNA levels. CTL, control. n = 4. (F) RNA dot blot analyses of PA28α and PA28β transcript levels. GAPDH and ribosome 18S RNA served as loading controls. (G) Reciprocal IP with PA28α and PA28β antibodies showed increased PA28α-associated PA28β and PA28β-associated PA28α in myocardium with PA28αOE.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts