Published Online
on November 19, 2007

A more recent version of this article appeared on December 11, 2007

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Submitted on July 17, 2007
Accepted on October 9, 2007

NF-B Is a Key Mediator of Cerebral Aneurysm Formation

Tomohiro Aoki MD, Hiroharu Kataoka MD, PhD^*, Munehisa Shimamura MD, PhD, Hironori Nakagami MD, PhD, Kouji Wakayama MD, Takuya Moriwaki MD, PhD, Ryota Ishibashi MD, Kazuhiko Nozaki MD, PhD, Ryuichi Morishita MD, PhD, and Nobuo Hashimoto MD, PhD

From the Department of Neurosurgery, Kyoto University, Graduate School of Medicine, Kyoto (T.A., H.K., T.M., R.I., K.N., N.H.); Department of Advanced Clinical Science and Therapeutics, Tokyo University, Graduate School of Medicine, Tokyo (M.S., K.W.); and Department of Clinical Gene Therapy, Osaka University, Graduate School of Medicine, Osaka (H.N., R.M.), Japan.

^* To whom correspondence should be addressed. E-mail: kataoka{at}kuhp.kyoto-u.ac.jp.

Background—Subarachnoid hemorrhage caused by the rupture of cerebral aneurysm (CA) remains a life-threatening disease despite recent diagnostic and therapeutic advancements. Recent studies strongly suggest the active participation of macrophage-mediated chronic inflammatory response in the pathogenesis of CA. We examined the role of nuclear factor-B (NF-B) in the pathogenesis of CA formation in this study.

Methods and Results—In experimentally induced CAs in rats, NF-B was activated in cerebral arterial walls in the early stage of aneurysm formation with upregulated expression of downstream genes. NF-B p50 subunit–deficient mice showed a decreased incidence of CA formation with less macrophage infiltration into the arterial wall. NF-B decoy oligodeoxynucleotide also prevented CA formation when it was administered at the early stage of aneurysm formation in rats. Macrophage infiltration and expression of downstream genes were dramatically inhibited by NF-B decoy oligodeoxynucleotide. In human CA walls, NF-B also was activated, especially in the intima.

Conclusions—Our data indicate that NF-B plays a crucial role as a key regulator in the initiation of CA development by inducing some inflammatory genes related to macrophage recruitment and activation. NF-B may represent a therapeutic target of a novel medical treatment for CA.

Key words: aneurysm • experimental animal models • endothelium • inflammation • NF-kappa B

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