Peroxisome proliferator-activated receptor γ coactivator 1ß (PGC-1ß) protein attenuates vascular lesion formation by inhibition of chromatin loading of minichromosome maintenance complex in smooth muscle cells.
J Biol Chem
; 288(7): 4625-36, 2013 Feb 15.
Article
em En
| MEDLINE
| ID: mdl-23264620
ABSTRACT
Proliferation of vascular smooth muscle cells (VSMCs) in response to vascular injury plays a critical role in vascular lesion formation. Emerging data suggest that peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1) is a key regulator of energy metabolism and other biological processes. However, the physiological role of PGC-1ß in VSMCs remains unknown. A decrease in PGC-1ß expression was observed in balloon-injured rat carotid arteries. PGC-1ß overexpression substantially inhibited neointima formation in vivo and markedly inhibited VSMC proliferation and induced cell cycle arrest at the G(1)/S transition phase in vitro. Accordingly, overexpression of PGC-1ß decreased the expression of minichromosome maintenance 4 (MCM4), which leads to a decreased loading of the MCM complex onto chromatin at the replication origins and decreased cyclin D1 levels, whereas PGC-1ß loss of function by adenovirus containing PGC-1ß shRNA resulted in the opposite effect. The transcription factor AP-1 was involved in the down-regulation of MCM4 expression. Furthermore, PGC-1ß is up-regulated by metformin, and metformin-associated anti-proliferative activity in VSMCs is at least partially dependent on PGC-1ß. Our data show that PGC-1ß is a critical component in regulating DNA replication, VSMC proliferation, and vascular lesion formation, suggesting that PGC-1ß may emerge as a novel therapeutic target for control of proliferative vascular diseases.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
/
Cromatina
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Proteínas de Transporte
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Transativadores
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Regulação da Expressão Gênica
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Proteínas de Ligação a RNA
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Proteína 1 de Manutenção de Minicromossomo
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Miócitos de Músculo Liso
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Biol Chem
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Estados Unidos