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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1080.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Reduced Collagen Biosynthesis Is the Hallmark of Cerebral Aneurysm

Contribution of Interleukin-1β and Nuclear Factor-B

Tomohiro Aoki; Hiroharu Kataoka; Ryota Ishibashi; Kazuhiko Nozaki; Ryuuichi Morishita; Nobuo Hashimoto

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

Correspondence to Hiroharu Kataoka, MD, PhD, Department of Neurosurgery, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. E-mail kataoka{at}kuhp.kyoto-u.ac.jp

Background— Reduced extracellular matrix is a prominent feature of cerebral aneurysms (CAs). We previously reported excessive ECM degradation in CA walls. In the present study, we examined collagen biosynthesis in CA walls and the molecular mechanisms underlying it in CA progression.

Methods and Results— RT-PCR and immunohistochemistry showed reduced expression of procollagen type I, III, and lysyl oxidase (LOX) in CA walls. Treatment with the LOX inhibitor β-aminopropionitrile resulted in enhanced progression of CA. Expression of procollagen type I, III, and LOX was inhibited by interleukin-1β (IL-1β) in cultured rat aortic smooth muscle cells (RASMCs) in vitro. Nuclear factor -B (NF-B) was activated in IL-1β-stimulated RASMCs, and treatment with NF-B decoy oligodeoxynucleotides (ODN) restored reduced expression of procollagen type I, III, and LOX in vitro. NF-B decoy ODNs ameliorated the expression of procollagen type I, III, and LOX in CA walls in vivo.

Conclusions— Collagen biosynthesis was significantly inhibited at the transcriptional level and in the posttranscriptional enzymatic modification in CA walls through upregulated expression of IL-1β and the NF-B pathway. Reduced collagen biosynthesis may contribute to CA progression, and inhibition of this process may lead to the prevention of the progression and rupture of CAs.

Expression of procollagen type I, III, and lysyl oxidase (LOX) was reduced in cerebral aneurysms (CAs) through induced expression of interleukin-1β and the activation of nuclear factor-B. Inhibition of LOX led to enhanced CA progression. These data suggested that reduced collagen biosynthesis may contribute to CA progression.

Key Words: cerebral aneurysm • collagen • procollagen • lysyl oxidase • inflammation