title: 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.
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.
authors.affiliation: Cardiovascular Center, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Guo
authors.forename: Yanbo
authors.initials: Y
authors.lastname: Fan
authors.forename: Jifeng
authors.initials: J
authors.lastname: Zhang
authors.forename: Lin
authors.initials: L
authors.lastname: Chang
authors.forename: Jiandie D
authors.initials: JD
authors.lastname: Lin
authors.forename: Y Eugene
authors.initials: YE
authors.lastname: Chen
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002843:Chromatin / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000378:metabolism; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D026341:Minichromosome Maintenance 1 Protein / Q000378:metabolism*; D008954:Models, Biological; D032389:Myocytes, Smooth Muscle / Q000166:cytology*; D020411:Oligonucleotide Array Sequence Analysis; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins / Q000378:metabolism*; D051381:Rats; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D002843:Chromatin; D026341:Minichromosome Maintenance 1 Protein; C455622:PPARGC1B protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; D015534:Trans-Activators; D014157:Transcription Factors