Inhibition of non-Ras protein farnesylation reduces in-stent restenosis

Coats, Paul and Kennedy, Simon and Pyne, Susan and Wainwright, Cherry L and Wadsworth, Roger M (2008) Inhibition of non-Ras protein farnesylation reduces in-stent restenosis. Atherosclerosis, 197 (2). pp. 515-523. ISSN 0021-9150 (https://doi.org/10.1016/j.atherosclerosis.2007.06....)

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Abstract

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 μM) 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 μM FPT III significantly reduced neointimal growth. In vivo, 15 min local infusion of 25 μM 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.

ORCID iDs

Coats, Paul ORCID logoORCID: https://orcid.org/0000-0002-6035-675X, Kennedy, Simon, Pyne, Susan ORCID logoORCID: https://orcid.org/0000-0002-6608-9584, Wainwright, Cherry L and Wadsworth, Roger M;
CORE (COnnecting REpositories)