Prevention of abdominal aortic aneurysms by simultaneous inhibition of NFkappaB and ets using chimeric decoy oligonucleotides in a rabbit model.
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 NFkappaB 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 NFkappaB- 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 NFkappaB and ets using chimeric decoy ODN. Further modification of chimeric decoy ODN would be useful to treat AAA as a decoy-based therapy.
Miyake
T
T
Division of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
Aoki
M
M
Nakashima
H
H
Kawasaki
T
T
Oishi
M
M
Kataoka
K
K
Tanemoto
K
K
Ogihara
T
T
Kaneda
Y
Y
Morishita
R
R
D000818:Animals; D001012:Aorta, Abdominal / Q000000981:diagnostic imaging / Q000378:metabolism; D017544:Aortic Aneurysm, Abdominal / Q000000981:diagnostic imaging / Q000517:prevention & control*; D001665:Binding Sites; D018932:Chemokine CCL2 / Q000378:metabolism; D016384:Consensus Sequence; D004591:Electrophoresis, Polyacrylamide Gel; D015316:Genetic Therapy / Q000379:methods*; D007150:Immunohistochemistry / Q000379:methods; D007249:Inflammation; D008264:Macrophages / Q000276:immunology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D008856:Microscopy, Fluorescence; D023421:Models, Animal; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics*; D009841:Oligonucleotides / Q000008:administration & dosage* / Q000235:genetics; D050784:Proto-Oncogene Protein c-ets-1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D011817:Rabbits; D011859:Radiography; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection / Q000379:methods*; D014463:Ultrasonography; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D018932:Chemokine CCL2; D016328:NF-kappa B; D009841:Oligonucleotides; D050784:Proto-Oncogene Protein c-ets-1; D019010:Vascular Cell Adhesion Molecule-1; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2