1. ¹Division of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, Suita, Japan
2. ²Department of Geriatric Medicine, Graduate School of Medicine, Osaka University, Suita, Japan
3. ³Second Department of Surgery, Faculty of Medicine, Tottori University, Yonago, Japan
4. ⁴Division of Cardiovascular Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
5. ⁵Department of Pharmacy, Osaka University Hospital, Suita, Japan
6. ⁶Department of Cardiovascular Surgery, Kawasaki Medical School, Okayama, Japan
7. ⁷Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, Suita, Japan

Correspondence: Professor R Morishita, Division of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan. E-mail: morishit@cgt.med.osaka-u.ac.jp

Received 3 July 2005; Revised 2 November 2005; Accepted 9 November 2005; Published online 5 January 2006.

Abstract

Abdominal aortic aneurysm (AAA) is one of the major vascular diseases caused by atherosclerosis. Because treatment for AAA mainly consists of surgery to prevent deaths from AAA rupture and there is a conspicuous absence of alternative therapeutic strategies, the development of minimally invasive treatment is needed. To develop a novel therapeutic approach, we examined the simultaneous inhibition of the transcription factors NFB and ets, which regulate inflammation and matrix degradation, in a rabbit AAA model. In this study, we employed chimeric decoy oligodeoxynucleotides (ODN), containing the consensus sequences of both the NFB- and ets-binding sites, to inhibit both the transcription factors simultaneously. Using a delivery sheet, we examined the inhibitory effect of chimeric decoy ODN on aortic dilatation. Ultrasound and angiographic analysis demonstrated that treatment with chimeric decoy ODN significantly prevented the progression of elastase-induced aortic dilatation. The inhibitory effect of chimeric decoy ODN on aortic dilatation was also confirmed by histological studies. Treatment with chimeric decoy ODN reduced the activities of matrix metalloproteinase (MMP)-2 and MMP-9 and markedly inhibited the proteolysis of elastin as compared to scrambled decoy ODN. Interestingly, treatment with chimeric decoy ODN also suppressed VCAM-1 and MCP-1 gene expression, leading to inhibition of macrophage infiltration in the adventitia and media. The present study in a rabbit model provides a novel strategy to treat AAA by the simultaneous inhibition of both NFB and ets using chimeric decoy ODN. Further modification of chimeric decoy ODN would be useful to treat AAA as a decoy-based therapy.