Locally applied antisense oligonucleotide to pcna inhibits intimal hyperplasia formation in experimental vein grafts

Pflckgnmndt Development of graft stenoses due to intimai hyperplasia (IH) is a common cause of vein graft (VG) failure. The formation of IH is due to smooth muscle cell (SMC) proliferation and deposition of extracellular matrix. During SMC proliferation, proliferating cell nuclear antigen (PCNA) is an important intermediate in a common mitogenic pathway required by all growth factors. This study examines the effect of locally applied antiscnsc PCNA oligonucleotide on the development of experimental VG IH. Methods: Twcniy-six New Zealand White rabbits underwent jugular vein interposition grafting of their right common carotid artery. Ten animals were controls, ten had the outer surface of the graft coated with 30% pluronic gel (2.5ml), and six had 200μg of an 18 base jniiscnse PCNA oligonucleotide added to the gel. At 28 days the animals were sacrificed, ;uwl grafts were perfusion fixed, sectioned and stained. Medial and intimai dimensions were quantified using videomorphometry. The data are expressed as the mean ±SEM. Bysulteit There was a 28% reduction in IH when antisense is added to the gel (p<0.01 compared with controls/gel alone). Them was no difference in intimai thickness between controls and the gel (inly group. Intima! Thickness Medial Thickness Intimai Ratio Control 70±4 μm 65 ±5 μm 0.52 ±0.02 30% Plurnnic Gel 72±4 μm 58 ±6μm 0.55 ±0.03 Amiseiwe PCNA 50 ±4 tim 80 ±8 μm 0.38 ±0.02 Intimai Ratio=lnt Area/lnt+Med Areas:=p< 0.01 compared to controls/gel only by ANOVA. Conclusions: These results show that locally applied antisense PCNA oligonucleotide reduces the formation of IH in experimental VG.