Autophagy and p62 in cardiac proteinopathy

Qingwen Zheng, Huabo Su, Mark J. Ranek, Xuejun Wang

Research output: Contribution to journalArticlepeer-review

162 Scopus citations


Rationale: Recent studies suggest an important role of autophagy in protection against αB-crystallin-based (CryABR120G) desmin-related cardiomyopathies (DRC), but this has not been demonstrated in a different model of cardiac proteinopathy. Mechanisms underlying the response of cardiomyocytes to proteotoxic stress remain incompletely understood. Objective: Our first objective was to determine whether and how the autophagic activity is changed in a mouse model of desminopathy. We also investigated the role of p62 in the protein quality control of cardiomyocytes. Methods and Results: Using an autophagosome reporter and determining changes in LC3-II protein levels in response to lysosomal inhibition, we found significantly increased autophagic flux in mouse hearts with transgenic overexpression of a DRC-linked mutant desmin. Similarly, autophagic flux was increased in cultured neonatal rat ventricular myocytes (NRVMs) expressing a mutant desmin. Suppression of autophagy by 3-methyladenine increased, whereas enhancement of autophagy by rapamycin reduced the ability of a comparable level of mutant desmin overexpression to accumulate ubiquitinated proteins in NRVMs. Furthermore, p62 mRNA and protein expression was significantly up-regulated in cardiomyocytes by transgenic overexpression of the mutant desmin or CryABR120G both in intact mice and in vitro. The p62 depletion impaired aggresome and autophagosome formation, exacerbated cell injury, and decreased cell viability in cultured NRVMs expressing the misfolded proteins. Conclusions: Autophagic flux is increased in desminopathic hearts, and as previously suggested in CryAB R120G-based DRC, this increased autophagic flux serves as an adaptive response to overexpression of misfolded proteins. The p62 is up-regulated in mouse proteinopathic hearts. The p62 promotes aggresome formation and autophagy activation and protects cardiomyocytes against proteotoxic stress.

Original languageEnglish (US)
Pages (from-to)296-308
Number of pages13
JournalCirculation Research
Issue number3
StatePublished - Jul 22 2011
Externally publishedYes


  • aggresome
  • autophagy
  • desmin-related cardiomyopathy
  • p62/SQSTM1
  • ubiquitin

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine


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