Local application of rapamycin inhibits vein graft restenosis in rabbits

Abstract

Objective: The aim of this study was to investigate whether local application of rapamycin reduced neointimal formation in a rabbit model of venous disease.

Methods: Each rabbit (n = 30; 2.5-3.5 kg) received a treated and a control graft. For the treated graft, 0.3 rapamycin mg was applied locally in Pluronic gel. The control graft received only the Pluronic gel. Grafts were harvested at 28 days for morphometric, immunohistochemical, and flow cytometry analysis.

Results: In the control group, the intimal thickness was 63.72 ± 14.0 μm; in treated group, it was 77.76 ± 14.9 μm (P < .05). Immunohistochemically, proliferation cell nuclear antigen-positive cells were present in the control group and in the treatment group but not in normal external jugular veins. The control group showed much stronger expression than the treatment group (P < .05). Flow cytometry showed, among the control group, decreased G(0)G(1)-stage cells and increased S/G(2)M-stage cells. Among the treatment group, S/G(2)M stage cells were decreased compared with the control. The progression indexes of the control and treatment groups were 29.3 ± 7.15 and 20.1 ± 9.48, respectively, a remarkable decrease (P < .05). Proliferating cells in the control group were apparently inhibited by rapamycin. The treatment group showed positive staining for P27(kip1), but neither the control group nor the normal external jugular veins showed positive results (P < .05). The degree of reduction in intimal thickness and inhibition of proliferating cells in the treatment group correlated with the expression of P27(kip1).

Conclusions: We observed that perivascular application of rapamycin inhibited neointimal hyperplasia of vein grafts in a rabbit model, an effect that appeared to result from increased P27(kip1) expression.