INHIBITION OF INTIMAL HYPERPLASIA BY AN ANTISENSE OLIGONUCLEOTIDE OF FARNESYL TRANSFERASE DELIVERED ENDOLUMINALLY DURING ILIAC ANGIOPLASTY IN A RABBIT MODEL

The major complication of vascular recanalization is intimal hyperplas ia which is due mainly to proliferation and migration of smooth muscle cells (SMC). Activation of SMC results from stimulation of protooncog ens (c-myb, c-myc, c-fos) by growth factors induced by activated ras-p roteins. Ras-proteins become activated after receiving a farnesyl grou p in a reaction catalyzed by farnesyl transferase. The purpose of this study was to test the effectiveness in preventing intimal hyperplasia of an antisense oligonucleotide of the alpha subunit of farnesyl-tran sferase delivered endoluminally during angioplasty of the common iliac artery in a rabbit model. Twenty-one male New Zealand rabbits with a mean weight of 3.3 kg fed a high cholesterol diet underwent bilateral angioplasty of the common iliac artery using hydrogel-coated balloon c atheters. On the right side three types of treatment were randomly per formed by adding one of the following three oligonucleotides to the hy drogel precoating: antisense oligonucleotide of farnesyl transferase ( n = 7), mismatch oligonucleotide (n = 7), and scramble oligonucleotide (n = 7). On the left side hydrogel was used with saline so that each animal served as its own control. Animals were killed 6 weeks after an gioplasty and arteries were studied. The thickness and mean surface of the neointima (MTI and MSI) and the ratio (R) of the neointima to neo intima + media were calculated. in the scramble and mismatch groups th ere was no difference between the treated and control arteries with re gard to MTI, MSI, or R. In the antisense group mean all three values w ere significantly lower on the treated side than the control side (EMI : p < 0.02, SMI: p < 0.02, and R: p < 0.01). Treated arteries in the a ntisense group presented significantly lower EMI (p < 0.02), SMI (p < 0.02), and R (p < 0.01) than treated arteries in the other groups wher eas the thickness and mean surface of the media were comparable. Endol uminal administration of an antisense oligonucleotide against the a su bunit of farneysyl transferase inhibited intimal hyperplasia in our mo del.