FoxO3 induces reversible cardiac atrophy and autophagy in a transgenic mouse model.
Cardiovasc Res
; 91(4): 587-97, 2011 Sep 01.
Article
en En
| MEDLINE
| ID: mdl-21628326
ABSTRACT
AIMS:
The transcription factor FoxO3 contributes to anti-hypertrophic signalling 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 ANDRESULTS:
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 foetal gene programme with increased expression of ß-myosin heavy chain and natriuretic peptides, and by the activation of AKT and mammalian target of rapamycin signalling. 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 1 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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Autofagia
/
Factores de Transcripción Forkhead
/
Miocardio
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Cardiovasc Res
Año:
2011
Tipo del documento:
Article
País de afiliación:
Alemania