Autophagy and p62 in Cardiac Proteinopathy
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: First, to determine whether and how the autophagic activity is changed in a mouse model of desminopathy; second, to investigate 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 upregulated 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 CryABR120G-based DRC, this increased autophagic flux serves as an adaptive response to overexpression of misfolded proteins. The p62 is upregulated in mouse proteinopathic hearts. The p62 promotes aggresome formation and autophagy activation and protects cardiomyocytes against proteotoxic stress.
- Received March 11, 2011.
- Revision received May 11, 2011.
- Accepted May 27, 2011.
- © 2011 American Heart Association, Inc.