Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 28, Pages 9745-9750Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0706802105
Keywords
protein aggregation; remodeling
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Funding
- NHLBI NIH HHS [HL-080144, R01 HL075173, HL-063834, R01 HL072016, HL-006296, HL-072016, R01 HL080144, P01 HL006296, HL-075173, R01 HL063834] Funding Source: Medline
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A missense mutation in the alpha B-crystallin (CryAB) gene triggers a severe form of desmin-related cardiomyopathy (DRCM) characterized by accumulation of misfolded proteins. We hypothesized that autophagy increases in response to protein aggregates and that this autophagic activity is adaptive. Mutant CryAB (CryAB(R120G)) triggered a >2-fold increase in cardiomyocyte autophagic activity, and blunting autophagy increased the rate of aggregate accumulation and the abundance of insoluble CryAB(R120G)-associated aggregates. Cardiomyocyte-restricted overexpression of CryAB(R120G) in mice induced intracellular aggregate accumulation and systolic heart failure by 12 months. As early as 2 months (well before the earliest declines in cardiac function), we detected robust autophagic activity. To test the functional significance of autophagic activation, we crossed CryAB(R120G) mice with animals harboring heterozygous inactivation of beclin 1, a gene required for autophagy. Blunting autophagy in vivo dramatically hastened heart failure progression with a 3-fold increase in interstitial fibrosis, greater accumulation of polyubiquitinated proteins, larger and more extensive intracellular aggregates, accelerated ventricular dysfunction, and early mortality. This study reports activation of autophagy in DRCM. Further, our findings point to autophagy as an adaptive response in this proteotoxic form of heart disease.
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