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(Circulation Research. 2007;101:1175.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Regression of Abdominal Aortic Aneurysms by Simultaneous Inhibition of Nuclear Factor B and Ets in a Rabbit Model

Takashi Miyake, Motokuni Aoki, Hisao Masaki, Tomio Kawasaki, Masako Oishi, Kazusaburo Kataoka, Toshio Ogihara, Yasufumi Kaneda, Ryuichi Morishita

From the Departments of Clinical Gene Therapy (T.M., R.M.) and Geriatric Medicine (T.O.) and Divisions of Cardiovascular Surgery (T.K.) and Gene Therapy Science (Y.K.), Graduate School of Medicine, Osaka University; Department of Physical Therapy (M.A.), Morinomiya University of Medical Sciences, Osaka; Department of Cardiovascular Surgery (H.M.), Kawasaki Medical School, Okayama; and Department of Pharmacy (M.O., K.K.), Osaka University Hospital, Japan.

Correspondence to Ryuichi Morishita, MD, PhD, 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

Because current therapy to treat abdominal aortic aneurysm (AAA), and particularly to manage small AAA, is limited to elective surgical repair, we explored less invasive molecular therapy by simultaneous inhibition of the transcription factors nuclear factor (NF)B and ets using a decoy strategy. Both NFB and ets were shown to be markedly activated in human AAA. In addition, NFB- and ets-positive cells were increased in the aneurysm wall, and a part of the expression of NFB and ets was detected in migrating macrophages. Thus, we used chimeric decoy oligodeoxynucleotides (ODNs) containing consensus sequences of both NFB and ets binding sites to treat AAA. Inhibitory effects of chimeric decoy ODNs on matrix metalloproteinase-1 and -9 expression were confirmed by ex vivo experiments using a human aorta organ culture. To examine the regressive effect in a rabbit already-formed AAA model, transfection by wrapping a delivery sheet containing chimeric decoy ODNs around the aneurysm was performed 1 week after incubation with elastase. Importantly, treatment with chimeric decoy ODNs significantly decreased the size of AAA. Interestingly, significant preservation of elastic fibers was observed with chimeric decoy ODN treatment, accompanied by a reduction of matrix metalloproteinase-2 and -9 and induction of macrophage apoptosis. Regression of AAA was also associated with an increase in elastin and collagen type I and III synthesis in the aneurysm wall. Minimally invasive molecular therapy targeted to the inhibition of NFB and ets is expected to be useful for AAA through the rebalance of matrix synthesis and degradation.

Key Words: gene therapy • aneurysm • nuclear factor B • ets • decoy