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Autophagy and p62 in cardiac proteinopathy

Qingwen Zheng1, Huabo Su, Mark J Ranek

  • 1Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, 414 East Clark Street, Vermillion, SD 57069, USA.

Circulation Research
|June 11, 2011
PubMed

Insights

Autophagy increases in desminopathy hearts to clear misfolded proteins. The protein p62 aids this process, protecting heart cells from damage and improving their survival.

Area of Science:

  • Cardiovascular Biology
  • Cellular Biology
  • Molecular Medicine

Background:

  • Autophagy plays a role in desmin-related cardiomyopathies (DRC), but its mechanisms in other cardiac proteinopathies are unclear.
  • Understanding cardiomyocyte response to proteotoxic stress is crucial for developing treatments.

Purpose of the Study:

  • Investigate autophagic activity changes in a mouse model of desminopathy.
  • Determine the role of p62 in cardiomyocyte protein quality control.

Main Methods:

  • Utilized an autophagosome reporter and LC3-II protein levels to assess autophagic flux.
  • Employed transgenic mouse models and cultured neonatal rat ventricular myocytes (NRVMs).
  • Manipulated autophagy using 3-methyladenine and rapamycin; assessed p62 expression and function.

Main Results:

  • Increased autophagic flux observed in mouse hearts and NRVMs overexpressing mutant desmin.
  • Autophagy suppression worsened mutant desmin accumulation, while enhancement reduced it.
  • p62 (sequestosome 1) expression was upregulated, and its depletion impaired aggresome-autophagy pathway, increasing cell injury.

Conclusions:

  • Increased autophagic flux is an adaptive response to misfolded proteins in desminopathic hearts.
  • p62 is upregulated in proteinopathic hearts and promotes aggresome formation and autophagy.
  • p62 protects cardiomyocytes against proteotoxic stress, highlighting its therapeutic potential.
Abstract

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