Local applied slow-releasing rapamycin inhibits neointima hyperplasia in vein graft

Abstract

To investigate whether rapamycin (RPM) can reduce the neointima formation in the autologous vein graft, thus to provide support for its clinical application. Twenty-four male rabbits were made external jugular vein-to-common carotid artery models and then were divided into 4 equal groups at random: blank-control group; F-127 control group receiving local application of 0.5 ml 20% F-127 around the vein graft; low-dose RPM group, receiving local application of 0.5 ml 20% F-127 containing RPM of 50 microg/cm(2); and high dose RPM group, receiving local application of 0.5 ml 20% F-127 containing RPM of 100 microg/cm2. The rabbits were killed 3 weeks later and the samples of vein graft bridge were taken to undergo light microscopy. The ratio of intima to media thickness and restenosis rate (ratio of lumina to lumina plus intima area) were measured. Immunohistochemistry was used to detect the proliferating cell nuclear antigen (PCNA) positive cells so as to indicate the degree of cell proliferation. The apoptosis cells were detected by TUNEL to indicate the degree of cell apoptosis. The intima thickness levels of the low- and high-dose RPM groups were 29 microm +/- 10 microm and 16 microm +/- 8 microm respectively, both significantly lower than those of the blank-control group and F-127 control group (90 microm +/- 11 microm and 85 microm +/- 11 microm respectively, all P < 0.05). The restenosis rate (lumina area/total area ratio) of the low- and high-dose RPM groups were 0.80 +/- 0.36 and 0.91 +/- 0.13 respectively, both significantly higher than those of the blank-control group and F-127 control group (0.58 +/- 0.11 and 0.65 +/- 0.47 respectively, all P < 0.05). The cell proliferation indicis of vascular smooth muscle cells (VSMCs) of the low- and high-dose RPM groups were 20% +/- 9% and 14% +/- 6% respectively, both significantly lower than those of the blank-control group and F-127 control group (31% +/- 7% and 35% +/- 6%, all P < 0.05). The cell apoptosis indicis of the low- and high-dose RPM groups were 33% +/- 7% and 36% +/- 7% respectively, both significantly lower than those of the blank-control group and F-127 control group (16% +/- 6% and 18.% +/- 8% respectively, all P < 0.05). Local delivery of slow-releasing RPM by F-127 effectively inhibits the neointima hyperplasia in vein graft by a mechanism of reducing the VSMC proliferation and inducing cell apoptosis.