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.

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.