Epothilone B inhibits neointimal formation after rat carotid injury through the regulation of cell cycle-related proteins.
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.
Lim
Yong
Y
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.
Kim
Tack-Joong
TJ
Jin
Yong-Ri
YR
Kim
Dong-Woon
DW
Kwon
Jin-Sook
JS
Son
Ju-Hee
JH
Jung
Jae-Chul
JC
Avery
Mitchell A
MA
Son
Dong Ju
DJ
Hong
Jin Tae
JT
Yun
Yeo-Pyo
YP
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
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