실험견에서 E2F Decoy 전이가 자가정핵 이식견의 내막과형성에 미치는 영향

Abstract

One of the leading causes of coronary and peripheral vascular graft failure is intimal hyperplasia at the vascular anastomotic site. Double-stranded DNA with high affinity for E2F as decoy cis elements may block the activation of genes mediating the cell cycle, suggesting that it could possibly be an effective therapeutic agent for treating intimal hyperplasia. In order to evaluate the effect of E2F decoy in a large animal model, jugular vein to femoral artery interposition grafts in experimental dogs with 15-20 kg body weight were treated, with either heparin, E2F decoy oligodeoxynucleotides (ODN) or mismatched ODN by hemagglutinating virus of Japan (HVJ) -liposome method using pressure-mediated delivery. The animals were divided into four groups, depending on the method of treatment and duration of observation. Group 1 (n= 3): heparin treated, four months after bypass, Group 2 (n= 3): E2F treated, four weeks after bypass, Group 3 (n= 4): E2F treated, and Group 4 (n= 4): mismatched ODN treated, four months after bypass. Computerized planimetry was used to measure intimal and medial cross-sectional surface areas of each vessel. The intima/media area ratios were compared between the groups after bypass surgery. Treatment of grafts with E2F decoy resulted in a significant reduction of intimal thickness after four months (intima/media area ratio= 0.26 ± 0.11) compared with mismatched ODN-treated group (intima/media area ratio= 1.61 ± 0.28) or heparin alone group (intima/media area ratio=1.49 ± 0.29) (p= 0.000). There was no difference between group 2 (0.37 ± 0.32) and 3 (0.26 ± 0.11) and between proximal and distal anastomotic sites. The above results suggest that gene therapy of E2F decoy in vein graft could be a new therapeutic strategy to prolong the graft patency by suppressing the intimal hyperplasia.