Abstract 11702: Atg7-dependent Regulation of P62 in Mice Ameliorates Desmin Related Cardiomyopathy
Background: Autophagy is a cellular homeostatic mechanism that can eliminate damaged and potentially toxic proteins. We have noted impaired autophagic activity in a mutant αB-crystallin (CryABR120G) mouse model of desmin-related cardiomyopathy (DRC). p62 functions as a cargo for targeting ubiquitinated misfolded proteins to the autophagy system and has a crucial role in the removal of aggregated proteins. Previously, p62 was thought to be upregulated in CryABR120G mice. However, a mouse model of cardiac-specific basal autophagy in which p62 expression could be modulated is lacking.
Hypothesis: Atg7 expression-dependent regulation of p62 in mouse hearts or neonatal rat cardiomyocytes (NRC) will induce increased autophagy and ameliorate cardiac proteinopathy in a model of DRC.
Methods and Results: We generated an inducible-transgenic (Tg) mouse of the Atg7 protein by cardiac specific overexpression of the Atg7 gene. The Atg7-Tg mouse showed Atg7 protein dose-dependent expression of p62 levels, which could be switched off by doxycycline treatment. Adenoviral mediated overexpression of Atg7 in NRCs also showed dose-dependent increased expression of p62. Knockdown of p62 using siRNA in NRCs reduced Atg7-mediated increased autophagic flux. Overexpression of Atg7 in mice had no detectable effect on other proteins involved in the autophagy-lysosomal pathways and normal heart morphology and function was maintained. However, the Atg7 Tg mice hearts showed increased levels of p62 and basal autophagy as measured by increased autophagic flux activity and ultrastructural examination. We crossed the CryABR120G mice to Atg7 Tg mice to define the functional significance of increased basal autophagy in cardiac proteinopathy. Sustained Atg7-induced autophagy in CryABR120G hearts showed increased p62 expression, enhanced autophagic flux and ameliorated DRC associated cardiac dysfunction with prolongation of survival by 40%.
Conclusions: Cardiac-specific Atg7 inducible-Tg mice showed increased level of p62 expression and increased autophagic flux. Induced basal autophagy in Atg7-Tg mice can ameliorate cardiac proteinopathy in DRC. Targeting the overall autophagic state may be therapeutically effective in some stages of cardiac disease.
- © 2012 by American Heart Association, Inc.