Prevention of abdominal aortic aneurysms by simultaneous inhibition of NFκB and ets using chimeric decoy oligonucleotides in a rabbit model

• Published in: Gene therapy Vol. 13; no. 8; pp. 695 - 704
• Main Authors: MIYAKE, T, AOKI, M, NAKASHIMA, H, KAWASAKI, T, OISHI, M, KATAOKA, K, TANEMOTO, K, OGIHARA, T, KANEDA, Y, MORISHITA, R
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.04.2006
• Subjects: Abdominal aneurysm; Analysis; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Aneurysms; Aortic aneurysms; Applied cell therapy and gene therapy; Arteriosclerosis; Binding sites; Biological and medical sciences; Biotechnology; Care and treatment; Elastase; Elastin; Fundamental and applied biological sciences. Psychology; Gelatinase B; Gene expression; Gene therapy; Genetic aspects; Genetic transcription; Health aspects; Health. Pharmaceutical industry; Industrial applications and implications. Economical aspects; Macrophages; Matrix metalloproteinase; Medical sciences; Metalloproteinase; Metalloproteins; Monocyte chemoattractant protein 1; NF-κB protein; Oligonucleotides; Prevention; Proteolysis; Transcription factors; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Vascular cell adhesion molecule 1; Vascular diseases; Japan; ets; Rabbit; Cardiovascular disease; NFKB; Lagomorpha; Aortic aneurysm; Prevention; Vertebrata; Mammalia; matrix metalloproteinase; Models; Oligonucleotide; Transcription factor NFκB; Inhibition; Gene therapy; decoy
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/sj.gt.3302704

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 NFκB 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 NFκB- 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 NFκB and ets using chimeric decoy ODN. Further modification of chimeric decoy ODN would be useful to treat AAA as a decoy-based therapy.