Abstract 40: Induced Basal Autophagy in Atg7 Mice Ameliorates Cardiac Proteinopathy
Backgrounds: Basal autophagy is a cellular homeostatic mechanism that can eliminate damaged and potentially toxic proteins and organelles. We hypothesized that cardiac proteinopathies, such as desmin-related cardiomyopathy (DRC) that lead to accumulations of misfolded proteins, can trigger alterations in cardiomyocyte autophagy as an adaptive process. However, a mouse model of cardiac specific-induced basal autophagy is lacking and the effects of acute or chronic increased basal autophagy remains unclear.
Hypothesis: To determine whether induction of basal autophagy in the induced Atg7 mice can ameliorate cardiac proteinopathy in a model of DRC.
Methods and Results: The protein Atg7 is thought to be essential for autophagy and, in an attempt to induce high levels of basal autophagy we generated an inducible-transgenic (Tg) mouse. This mouse is able to undergo cardiac specific overexpression of the Atg7 gene, where the transgene can be switched on or off by doxycycline. The Atg7-Tg mouse showed 10 fold overexpression of Atg7 protein with normal heart morphology and function being maintained even after 10 months. Overexpression of Atg7 had no detectable effect on other proteins involved in the autophagy-lysosomal pathways. However, the hearts show increased basal autophagy, as measured by increased autophagic flux activity and cardiomyocyte ultrastructural examination. We showed earlier that autophagy can be down-regulated in cardiac proteinopathy as observed in a mutant αB-crystallin (CryABR120G) mouse model of DRC. Therefore, we crossed the CryABR120G mice to transgenic mice with cardiac specific overexpression of Atg7. Sustained Atg7-induced autophagy in CryABR120G hearts prolonged CryABR120G survival by 40% and is associated with the maintenance of cardiac function and decreased cardiac hypertrophy.
Conclusions: Cardiac-specific Atg7 inducible-Tg mice with increased basal autophagy may serve as a novel model to study the regulatory role of autophagy in the heart. Induced basal autophagy in Atg7-Tg mice can extend the life-span in a model of cardiac proteinopathy. Modulating the overall autophagic state may be useful therapeutically in heart disease.
- © 2012 by American Heart Association, Inc.