期刊
ATHEROSCLEROSIS
卷 197, 期 2, 页码 515-523出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.atherosclerosis.2007.06.007
关键词
coronary intervention; coronary disease; restenosis; signal transduction; stems
资金
- British Heart Foundation Funding Source: Medline
Ras has a key role in relation to cell proliferation, survival and migration and requires farnesylation for full activity. The effects of a Ras farnesyl transferase inhibitor, FPT III on human atherosclerotic vascular smooth muscle (VSM) cells proliferation and p42/p44 mitogen-activated protein kinase (p42/p44 MAPK) activity was measured. In addition the ability of FPT III to modify the development of neointimal growth was tested in cultured human arteries and in a rabbit model of in-stent restenosis. In human VSM cells FPT III (25 mu M) inhibited FCS-stimulated cell proliferation through a ras-dependent mechanism (after 18 h exposure) and also a novel ras-independent mechanism (following 15 min exposure). FPT III incubation (18 h) inhibited platelet-derived growth factor (PDGF)-stimulated p42/p44 MAPK activation and p21 Ras membrane localization, whereas 15 min incubation had no effect on the activation of p42/p44 MAPK in response to PDGF (added at 18 h) or on membrane p21 Ras localization (measured at 18 h). In cultured human atherosclerotic arteries, the presence of 25 mu M FPT III significantly reduced neointimal growth. In vivo, 15 min local infusion of 25 mu M FPT III significantly reduced in-stent restenosis 28 days later without affecting vascular function in normal rabbit artery. This study demonstrates that brief administration of a farnesyl transferase inhibitor reduced in-stent restenosis in a rabbit model without deleterious effects on vascular function or endothelial regrowth. Acute application of FPT III was found to act through a novel mechanism to inhibit smooth muscle cell proliferation via a non-ras pathway, which may contribute to the prevention of in-stent restenosis. (C) 2007 Elsevier Ireland Ltd. All rights reserved.
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