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 γ 1, and PDGF-receptor β 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.
Footnotes
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This study was supported by the program of the Research Center for Bioresource and Health, which is managed and funded by the Ministry of Science and Technology and the Korean Science and Engineering Foundation, and by a Korean Research Foundation Grant from the Korean Government (Basic Research Promotion Fund KRF-2005-005-J15002).
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Y.L. and T.-J.K. contributed equally to this work.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.117622.
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ABBREVIATIONS: VSMCs, vascular smooth muscle cells; PDGF, platelet-derived growth factor; CDK, cyclin-dependent protein kinase; Rb, retinoblastoma; DMEM, Dulbecco's modified Eagle's medium; ERK, extracellular signal-regulated kinase; PLC, phospholipase C; PDGF-Rβ, platelet-derived growth factor receptor β chain; MLD, mean luminal diameter; BrdU, 5-bromo-2′-deoxyuridine; FBS, fetal bovine serum; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PI, propidium iodide; PAGE, polyacrylamide gel electrophoresis; U0126, 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophynyltio)butadiene; LY294002, 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride; U73122, 1-[6-[[17β-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione; AU, arbitrary unit(s); AG1295, 6,7-dimethyl-2-phenylquinoxaline.
- Received November 24, 2006.
- Accepted February 7, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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