The Effect of Farnesyl Transferase Inhibitor on the Proliferation of Vascular Smooth Muscle Cells and Neointima Formation

Yoo, Byung Su; Yoon, Jung han; Kim, Jang Young; Choi, Hyun Min; Lee, Seung Hwan; Hwang, Sung Oh; Choe, Kyung Hoon; Ko, Jong Sung

Abstract

BACKGROUND AND OBJECTIVES
We tested the hypothesis that prolonged oral administration of farnesyl transferase inhibitor (FTI, LB42908a, MW=604, LG chemical, Korea) inhibits the proliferation and neointimal thickening of smooth muscle cells (SMC) in a rat carotid injury model.
MATERIALS AND METHODS
Cultured rat aortic vascular SMCs were exposed to sequential concentrations of FTI, and the proliferation inhibition analyzed using the MTT assay. In the rat carotid injury model, the FTI, at 3 dose levels (low-dose;10mg/kg, bid;mid-dose;50mg/kg, bid;high-dose;100 mg/kg, bid), or as a placebo, was administered orally, twice a day for 14 days, starting from 30 minutes before injury, until sacrifice. The histo-morphometric analysis was performed. The immunohistochemical detection of the proliferating cell nuclear antigen (PCNA) was performed for 3 days.
RESULTS
FTI inhibited the PDGF or FBS-induced cellular proliferations in a dose dependently manner. In the rat carotid artery balloon injury model, the mean neointimal area was significantly less in the mid-dose group than in the placebo and low-dose groups (control:0.35+/-0.04mm2, low-dose:0.23+/-0.04mm2 and mid-dose:0.19+/-0.04mm2, p<0.05), and the mean ratio of the neointima to medial areas were significantly less in the mid-dose group than in the placebo and low dose group (placebo:3.02+/-0.34, low-dose:2.24+/-0.54 and mid-dose:1.47+/-0.31, p<0.05). The labeling index of the PCNA was significantly less in the mid-dose group than in the placebo and low-dose groups (control:71+/-9, low-dose:73+/-9, mid-dose:54+/-14 and high-dose:53+/-9, p<0.05).
CONCLUSION
The FTI inhibits SMC proliferation in a dose dependent manner. The prolonged oral administration of FTI, for 14 days, is effective in reducing neointimal hyperplasia in the rat carotid balloon injury model.