Department of Neurosurgery, Kyoto University Graduate School of Medicine, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
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 beta-aminopropionitrile resulted in enhanced progression of CA. Expression of procollagen type I, III, and LOX was inhibited by interleukin-1beta (IL-1beta) in cultured rat aortic smooth muscle cells (RASMCs) in vitro. Nuclear factor kappa-B (NF-kappaB) was activated in IL-1beta-stimulated RASMCs, and treatment with NF-kappaB decoy oligodeoxynucleotides (ODN) restored reduced expression of procollagen type I, III, and LOX in vitro. NF-kappaB 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-1beta and the NF-kappaB 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.