title: Systemic administration of ribbon-type decoy oligodeoxynucleotide against nuclear factor κB and ets prevents abdominal aortic aneurysm in rat model.
abstract: Currently, there is no effective clinical treatment to prevent abdominal aortic aneurysm (AAA). To develop a novel therapeutic approach, we modified decoy oligodeoxynucleotide (ODN) against nuclear factor κB (NFκB) and ets, to a ribbon-shaped circular structure without chemical modification, to increase its resistance to endonuclease for systemic administration. Intraperitoneal administration of ribbon-type decoy ODNs (R-ODNs) was performed in an elastase-induced rat AAA model. Fluorescent isothiocyanate (FITC)-labeled R-ODNs could be detected in macrophages migrating into the aneurysm wall, and NFκB and ets activity were simultaneously inhibited by chimeric R-ODN. Treatment with chimeric R-ODN significantly inhibited aortic dilatation, whereas conventional phosphorothioate decoy ODN failed to prevent aneurysm formation. Significant preservation of elastic fibers was observed with chimeric R-ODN, accompanied by a reduction of secretion of several proteases from macrophages. Activation of matrix metalloproteinase (MMP)-9 and MMP-12, but not MMP-2, was suppressed in the aneurysm wall by chimeric R-ODN, whereas recruitment of macrophages was not inhibited. Treatment with chimeric R-ODN also inhibited the secretion of cathepsin B and K from macrophages. Overall, the present study demonstrated that systemic administration of chimeric R-ODNs prevented aneurysm formation in a rat model. Further modification of the decoy strategy would provide a means of less invasive molecular therapy for human AAA.
authors.affiliation: Department of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Miyake
authors.forename: Motokuni
authors.initials: M
authors.lastname: Aoki
authors.forename: Mariana K
authors.initials: MK
authors.lastname: Osako
authors.forename: Munehisa
authors.initials: M
authors.lastname: Shimamura
authors.forename: Hironori
authors.initials: H
authors.lastname: Nakagami
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Morishita
mesh_terms: D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D002401:Cathepsin B / Q000037:antagonists & inhibitors; D056657:Cathepsin K / Q000037:antagonists & inhibitors; D004720:Endonucleases / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D023421:Models, Animal; D058990:Molecular Targeted Therapy / Q000379:methods; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000737:chemistry* / Q000235:genetics; D010196:Pancreatic Elastase / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D050783:Proto-Oncogene Proteins c-ets; D004720:Endonucleases; D010196:Pancreatic Elastase; D002401:Cathepsin B; D056657:Cathepsin K; D020782:Matrix Metalloproteinases