Abstract 284: Regression of Abdominal Aortic Aneurysms by Simultaneous Inhibition of NFκB and Ets in a Rabbit Model
As current therapy to treat abdominal aortic aneurysm (AAA), and particularly to manage small AAA, is limited to elective surgical repair, we explored less invasive molecular therapy by simultaneous inhibition of the transcription factors, NFκB and ets, using a decoy strategy. Initially, we examined the expression of NFκB and ets in human AAA samples. Of importance, both NFκB and ets were shown to be markedly activated in the neck of AAA, the most active part of the lesion, using gel shift assay. In addition, immunohistochemical staining also demonstrated an increase in NFκB- and ets-positive cells in the aneurysm wall, and a part of the expression of NFκB and ets was detected in migrating macrophages. Thus, we focused on the simultaneous inhibition of both NFκB and ets, to treat AAA. To achieve this, we employed chimeric decoy oligodeoxynucleotides (ODN) containing consensus sequences of both NFκB and ets binding sites. Inhibitory effects of chimeric decoy ODN on matrix metalloproteinases (MMP)-1 and MMP-9 expression in a dose-dependent manner were confirmed by ex vivo experiments using a human aorta organ culture (P<0.01). To examine the regressive effect of chimeric decoy ODN in a rabbit already-formed AAA model, transfection by wrapping a delivery sheet containing chimeric decoy ODN around the aneurysm was performed one week after incubation with elastase. Importantly, treatment with chimeric decoy ODN significantly regressed the size of AAA in a dose-dependent manner as assessed by ultrasonography and angiography (P<0.01). Interestingly, significant preservation of elastic fibers was observed with chimeric decoy ODN treatment (P<0.0005), accompanied by a reduction of MMP-2 and MMP-9 and induction of macrophage apoptosis, leading to inhibition of macrophage accumulation (P<0.05). Regression of AAA was also associated with an increase in elastin (P<0.05) and collagen type I and III synthesis (P<0.05) in the aneurysm wall. Here, we demonstrated significant regression of AAA by the simultaneous inhibition of both NFκB and ets using a chimeric decoy strategy. Minimally invasive molecular therapy targeted to the inhibition of NFκB and ets is expected to be useful for AAA through the re-balance of matrix synthesis and degradation.