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Autophagy is an adaptive response in desmin-related cardiomyopathy. Proc Natl Acad Sci U S A 2008 Jul 15;105(28):9745-50

Date

07/16/2008

Pubmed ID

18621691

Pubmed Central ID

PMC2474535

DOI

10.1073/pnas.0706802105

Scopus ID

2-s2.0-47749125013   176 Citations

Abstract

A missense mutation in the alphaB-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.

Author List

Tannous P, Zhu H, Johnstone JL, Shelton JM, Rajasekaran NS, Benjamin IJ, Nguyen L, Gerard RD, Levine B, Rothermel BA, Hill JA

Author

Ivor J. Benjamin MD Center Director, Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Autophagy
Cardiomyopathies
Desmin
Fibrosis
Mice
Mice, Mutant Strains
Mutation, Missense
Myocytes, Cardiac
Polyubiquitin
alpha-Crystallin B Chain
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a