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(Circulation. 2004;109:132-138.)
© 2004 American Heart Association, Inc.

Basic Science Reports

Inhibition of Experimental Abdominal Aortic Aneurysm in the Rat by Use of Decoy Oligodeoxynucleotides Suppressing Activity of Nuclear Factor B and ets Transcription Factors

Hideki Nakashima, MD^*; Motokuni Aoki, MD, PhD^*; Takashi Miyake, MD; Tomio Kawasaki, MD, PhD; Masahiro Iwai, PhD; Nobuo Jo, MD; Masako Oishi, PhD; Kazusaburo Kataoka, PhD; Shigetsugu Ohgi, MD, PhD; Toshio Ogihara, MD, PhD; Yasufumi Kaneda, MD, PhD; Ryuichi Morishita, MD, PhD

From the Division of Gene Therapy Science (H.N., N.J., Y.K.), the Department of Geriatric Medicine (M.A., T.O.), the Division of Clinical Gene Therapy (T.M., R.M.), the Division of Cardiovascular Surgery (M.I.), and the Department of Pharmacy (H.N., M.O., K.K.), Graduate School of Medicine, Osaka University, Osaka, Japan; Ono Pharmaceutical Company Ltd (M.I.), Osaka, Japan; and the Second Department of Surgery (S.O.), Faculty of Medicine, Tottori University, Yonago, Japan.

Correspondence to Dr Ryuichi Morishita, Division of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan. E-mail morishit{at}cgt.med.osaka-u.ac.jp

Received July 26, 2003; de novo received April 16, 2003; revision received August 25, 2003; accepted August 26, 2003.

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)–B, 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-B and ets by using chimeric decoy oligodeoxynucleotides (ODN).

Methods and 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-B 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-B 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-B and ets in rat model. NF-B and ets are considered to play an important role in the pathogenesis of AAA.

Key Words: aneurysm • aorta • inflammation • gene therapy • metalloproteinase

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