Abstract 430: Inhibition of Aneurysm Development by Intra-peritoneal Application of Ribbon-type Decoy Oligodeoxynucleotide against Nuclear Factor-κB and Ets in a Rat Model
As elective surgical or endovascular repair is not effective to improve survival of small abdominal aortic aneurysm (AAA), the development of a novel therapeutic approach for treating small AAA is awaited. We have previously reported the regressive effect of chimeric decoy oligodeoxynucleotides (ODN) against NFκB and ets in an experimental AAA model. However, local application of conventional phosphorothioated chimeric decoy ODN (PC-ODN) was necessary due to easily degradation. Therefore, we developed a novel chimeric decoy ODN with a ribbon-shaped circular structure (RC-ODN) to stabilize decoy ODN against nucleases. Transfection of RC-ODN inhibited MMP-2 expression in VSMC, but not MMP-9 expression. In contrast, in cultured THP-1 cells, MMP-9 expression was suppressed by RC-ODN, whereas MMP-2 expression was not altered. Interestingly, these inhibitory effects of RC-ODN were more potent than that of PC-ODN (n=8, P<0.05). Next, intra-peritoneal application of RC-ODN was performed in an elastase-induced rat AAA model. One week after injection, FITC-labeled RC-ODN were detected in migrating macrophages into aneurysm wall. In addition, both NFκB and ets activity were suppressed by RC-ODN. Four weeks after treatment, RC-ODN treatment inhibited the aortic dilatation as compared to control or scrambled decoy ODN transfer (n=6, P<0.05), while PC-ODN treatment failed to prevent aneurysm formation. Interestingly, a significant preservation of elastic fibers was observed with RC-ODN treatment, accompanied by a reduction of expression of MMP-9, MMP-12, cathepsin B and cathepsin K (P<0.05), while the recruitment of macrophages was not inhibited. Finally, to consider the clinical application, we investigated the effect of intravenous injection of RC-ODN. Four weeks after infusion of angiotensin II in apolipoprotein E-deficient mice, intravenous injection of RC-ODN (1 mg/Kg) was performed 3 times per week. RC-ODN treatment showed a tendency to decrease the size of AAA, but not significant. In conclusion, the present study provided a novel strategy to treat AAA using intra-peritoneal application of RC-ODN in a rat model. Further development of this strategy would be useful to treat human AAA, as a minimally invasive molecular therapy.