Inhibition of experimental abdominal aortic aneurysm in the rat by use of decoy oligodeoxynucleotides suppressing activity of nuclear factor kappaB and ets transcription factors.
BACKGROUND
Two phenomena, inflammation and matrix degradation, contribute to the progression of abdominal aortic aneurysm (AAA). Importantly, the inflammation is regulated by the transcription factor nuclear factor (NF)-kappaB, whereas the destruction and degradation of elastin fibers by matrix metalloproteinases (MMP) are regulated by ets. Thus, we developed a novel strategy to treat AAA by simultaneous inhibition of both NF-kappaB and ets by using chimeric decoy oligodeoxynucleotides (ODN).


RESULTS
AAA was induced in rats by transient aortic perfusion with elastase, whereas transfection of decoy ODN was performed by wrapping a delivery sheet containing decoy ODN around the aorta. Gel-mobility shift assay at 7 days after treatment demonstrated that both NF-kappaB and ets binding activity were simultaneously inhibited by chimeric decoy ODN. Transfection of chimeric decoy ODN resulted in significant inhibition of the progression of AAA such as aneurysmal dilation at 4 weeks after treatment as compared with control, accompanied by a reduction of MMP expression. Moreover, the destruction of elastin fibers was inhibited in the aorta transfected with chimeric decoy ODN. Importantly, transfection of chimeric decoy ODN demonstrated potent inhibition of aneurysmal dilatation compared with NF-kappaB decoy ODN alone, whereas scrambled decoy ODN had no effects. Interestingly, the migration of macrophages was significantly inhibited by chimeric decoy ODN.


CONCLUSIONS
We demonstrated that inhibition of the progression of AAA was achieved by a novel strategy with chimeric decoy ODN used against NF-kappaB and ets in rat model. NF-kappaB and ets are considered to play an important role in the pathogenesis of AAA.
Nakashima
Hideki
H
Division of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
Aoki
Motokuni
M
Miyake
Takashi
T
Kawasaki
Tomio
T
Iwai
Masahiro
M
Jo
Nobuo
N
Oishi
Masako
M
Kataoka
Kazusaburo
K
Ohgi
Shigetsugu
S
Ogihara
Toshio
T
Kaneda
Yasufumi
Y
Morishita
Ryuichi
R
D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000000981:diagnostic imaging / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D016328:NF-kappa B / Q000235:genetics / Q000502:physiology*; D009838:Oligodeoxyribonucleotides; D051381:Rats; D017208:Rats, Wistar; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014463:Ultrasonography
D016328:NF-kappa B; C468119:NF-kappaB decoy; D009838:Oligodeoxyribonucleotides; D014157:Transcription Factors; D020782:Matrix Metalloproteinases