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FoxO3 Induces Reversible Cardiac Atrophy and Autophagy in a Transgenic Mouse Model.
MedLine Citation:
PMID:  21628326     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Aims The transcription factor FoxO3 contributes to anti-hypertrophic signaling in the heart presumably by regulating autophagic-lysosomal and ubiquitin-proteasomal pathways. We wanted to study FoxO3 function in the adult heart in vivo by expressing a constitutively active mutant of FoxO3 in transgenic mice. Methods and Results We generated transgenic mice in which a tetracycline-regulated constitutively active FoxO3 transgene (FoxO3-CA) is controlled by the heart-specific α-myosin heavy chain promoter. Cardiac-specific expression in adult mice resulted in a decrease in heart weight by 25% and a reduction in stroke volume and cardiac output. The decrease in heart size was due to a reduction in the size of individual cardiomyocytes, whereas there was no evidence for increased cell death. FoxO3 activation was accompanied by the initiation of a fetal gene program with increased expression of β-myosin heavy chain and natriuretic peptides, and by the activation of AKT and mammalian target of rapamycin signaling. As shown by electron microscopy, FoxO3-CA massively stimulated destruction of sarcomeres and autophagy, and induced expression of LC3-II and BNIP3. When FoxO3-CA expression was shut off in affected mice, cardiac atrophy and dysfunction as well as molecular markers were normalized within one month. FoxO3-CA expression did not counteract hypertrophy induced by transverse aortic constriction. Conclusion Heart-specific expression of constitutively active FoxO3 leads to reversible heart atrophy. The reversibility of the phenotype suggests a remarkable ability of the adult myocardium to respond to different regulatory cues.
Authors:
Tobias G Schips; Astrid Wietelmann; Katharina Höhn; Silvia Schimanski; Paul Walther; Thomas Braun; Thomas Wirth; Harald J Maier
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-5-30
Journal Detail:
Title:  Cardiovascular research     Volume:  -     ISSN:  1755-3245     ISO Abbreviation:  -     Publication Date:  2011 May 
Date Detail:
Created Date:  2011-6-1     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Institute of Physiological Chemistry, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
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