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J Biol Chem. 2013 Feb 15;288(7):4625-36. doi: 10.1074/jbc.M112.407452. Epub 2012 Dec 21.

Peroxisome proliferator-activated receptor γ coactivator 1β (PGC-1β) protein attenuates vascular lesion formation by inhibition of chromatin loading of minichromosome maintenance complex in smooth muscle cells.

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  • 1Cardiovascular Center, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.

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-1β in VSMCs remains unknown. A decrease in PGC-1β expression was observed in balloon-injured rat carotid arteries. PGC-1β 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-1β 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-1β loss of function by adenovirus containing PGC-1β shRNA resulted in the opposite effect. The transcription factor AP-1 was involved in the down-regulation of MCM4 expression. Furthermore, PGC-1β is up-regulated by metformin, and metformin-associated anti-proliferative activity in VSMCs is at least partially dependent on PGC-1β. Our data show that PGC-1β is a critical component in regulating DNA replication, VSMC proliferation, and vascular lesion formation, suggesting that PGC-1β may emerge as a novel therapeutic target for control of proliferative vascular diseases.

PMID:
23264620
[PubMed - indexed for MEDLINE]
PMCID:
PMC3576068
Free PMC Article
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