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CARDIOVASCULAR

Epothilone B Inhibits Neointimal Formation after Rat Carotid Injury through the Regulation of Cell Cycle-Related Proteins

College of Pharmacy, Research Center for Bioresource and Health (Y.L., T.-J.K., D.J.S., J.T.H., Y.-P.Y.), Research Institute of Veterinary Medicine (Y.-R.J.), and Department of Internal Medicine, College of Medicine (D.-W.K., J.-S.K., J.-H.S.), Chungbuk National University, Cheongju, Korea; and Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, Jackson, Mississippi (J.-C.J., M.A.A.)

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 1, and PDGF-receptor 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.

Address correspondence to: Dr. Yeo-Pyo Yun, College of Pharmacy, Chungbuk National University, 12 Gaeshin-Dong, Heungduk-Gu, Cheongju 361-763, Korea. E-mail: ypyun{at}chungbuk.ac.kr