title: Epothilone B inhibits neointimal formation after rat carotid injury through the regulation of cell cycle-related proteins.
abstract: The abnormal proliferation of vascular smooth muscle cells (VSMCs) in arterial walls is an important pathogenetic factor of vascular disorders such as atherosclerosis and restenosis after angioplasty. Epothilone B, a novel potential antitumor compound, has a potent effect on preventing postangioplasty restenosis. Therefore, we established an in vivo rat carotid injury model and examined the potential effects of epothilone B on cardiovascular disease. We found that epothilone B potently prevented neointimal formation and in vivo VSMCs proliferation. In addition, we also showed that epothilone B significantly inhibited 5% fetal bovine serum (FBS)- and 50 ng/ml platelet-derived growth factor (PDGF)-BB-induced proliferation and cell cycle progression in rat aortic VSMCs. Furthermore, FBS and PDGF-BB induced the activations of extracellular signal-regulated kinases 1 and 2, Akt, phospholipase C gamma 1, and PDGF-receptor beta chain tyrosine kinase were not changed by epothilone B. However, epothilone B treatment caused a significant decrease in the level of cyclin-dependent protein kinase (CDK) 2, whereas it caused no change in the levels of cyclin E and down-regulated the phosphorylation of retinoblastoma, which plays a critical role in cell cycle regulation. Furthermore, levels of p27, an inhibitor of cyclin E/CDK2 complex, were significantly increased in VSMCs treated with epothilone B, indicating that this might be a major molecular mechanism for the inhibitory effects of epothilone B on the proliferation and cell cycle of VSMCs. These findings suggest that epothilone B can inhibit neointimal formation via the cell cycle arrest by the regulation of the cell cycle-related proteins in VSMCs.
authors.affiliation: College of Pharmacy, Research Center for Bioresource and Health, Research Institute of Veterinary Medicine, and Department of Internal Medicine, Chungbuk National University, 12 Gaeshin-Dong, Heungduk-Gu, Cheongju 361-763, Korea.
authors.forename: Yong
authors.initials: Y
authors.lastname: Lim
authors.forename: Tack-Joong
authors.initials: TJ
authors.lastname: Kim
authors.forename: Yong-Ri
authors.initials: YR
authors.lastname: Jin
authors.forename: Dong-Woon
authors.initials: DW
authors.lastname: Kim
authors.forename: Jin-Sook
authors.initials: JS
authors.lastname: Kwon
authors.forename: Ju-Hee
authors.initials: JH
authors.lastname: Son
authors.forename: Jae-Chul
authors.initials: JC
authors.lastname: Jung
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Avery
authors.forename: Dong Ju
authors.initials: DJ
authors.lastname: Son
authors.forename: Jin Tae
authors.initials: JT
authors.lastname: Hong
authors.forename: Yeo-Pyo
authors.initials: YP
authors.lastname: Yun
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000473:pathology; D020212:Carotid Artery Injuries / Q000188:drug therapy* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis; D034261:Epothilones / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000473:pathology; D051966:Phospholipase C gamma / Q000502:physiology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology
chemical_list: C493962:Cdkn1b protein, rat; D034261:Epothilones; D016160:Retinoblastoma Protein; D050760:Cyclin-Dependent Kinase Inhibitor p27; D020797:Receptor, Platelet-Derived Growth Factor beta; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2; D048049:Extracellular Signal-Regulated MAP Kinases; D051966:Phospholipase C gamma; C093788:epothilone B