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 hyperplasia which is due mainly to proliferation and migration of smooth muscle cells (SMC). Activation of SMC results from stimulation of protooncogens (c-myb, c-myc, c-fos) by growth factors induced by activated ras-proteins. Ras-proteins become activated after receiving a farnesyl group 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-transferase 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 catheters. On the right side three types of treatment were randomly performed by adding one of the following three oligonucleotides to the hydrogel 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 angioplasty and arteries were studied. The thickness and mean surface of the neointima (MTI and MSI) and the ratio (R) of the neointima to neointima + media were calculated. in the scramble and mismatch groups there was no difference between the treated and control arteries with regard to MTI, MSI, or R. In the antisense group mean all three values were 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 antisense group presented significantly lower EMI (p < 0.02), SMI (p < 0.02), and R (p < 0.01) than treated arteries in the other groups whereas the thickness and mean surface of the media were comparable. Endoluminal administration of an antisense oligonucleotide against the a subunit of farneysyl transferase inhibited intimal hyperplasia in our model.