Systemic administration of ribbon-type decoy oligodeoxynucleotide against nuclear factor κB and ets prevents abdominal aortic aneurysm in rat model.
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.
Miyake
Takashi
T
Department of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Aoki
Motokuni
M
Osako
Mariana K
MK
Shimamura
Munehisa
M
Nakagami
Hironori
H
Morishita
Ryuichi
R
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
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