PMID- 27349749 OWN - NLM STAT- MEDLINE DCOM- 20171010 LR - 20181113 IS - 1742-2094 (Electronic) IS - 1742-2094 (Linking) VI - 13 IP - 1 DP - 2016 Jun 27 TI - Hyperhomocysteinemia induced by excessive methionine intake promotes rupture of cerebral aneurysms in ovariectomized rats. PG - 165 LID - 10.1186/s12974-016-0634-3 [doi] LID - 165 AB - BACKGROUND: Hyperhomocysteinemia (HHcy) is associated with inflammation and a rise in the expression of matrix metalloproteinase-9 (MMP-9) in the vascular wall. However, the role of HHcy in the growth and rupture of cerebral aneurysms remains unclear. METHODS: Thirteen-week-old female Sprague-Dawley rats were subject to bilateral ovariectomy and ligation of the right common carotid artery and fed an 8 % high-salt diet to induce cerebral aneurysms. Two weeks later, they underwent ligation of the bilateral posterior renal arteries. They were divided into two groups and methionine (MET) was or was not added to their drinking water. In another set of experiments, the role of folic acid (FA) against cerebral aneurysms was assessed. RESULTS: During a 12-week observation period, subarachnoid hemorrhage due to aneurysm rupture was observed at the anterior communicating artery (AcomA) or the posterior half of the circle of Willis. HHcy induced by excessive MET intake significantly increased the incidence of ruptured aneurysms at 6-8 weeks. At the AcomA of rats treated with MET, we observed the promotion of aneurysmal growth and infiltration by M1 macrophages. Furthermore, the mRNA level of MMP-9, the ratio of MMP-9 to the tissue inhibitor of metalloproteinase-2, and the level of interleukin-6 were higher in these rats. Treatment with FA abolished the effect of MET, suggesting that the inflammatory response and vascular degradation at the AcomA is attributable to HHcy due to excessive MET intake. CONCLUSIONS: We first demonstrate that in hypertensive ovariectomized rats, HHcy induced by excessive MET intake may be associated with the propensity of the aneurysm wall to rupture. FAU - Korai, Masaaki AU - Korai M AD - Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan. komakun@gmail.com. AD - Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA. komakun@gmail.com. FAU - Kitazato, Keiko T AU - Kitazato KT AD - Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan. FAU - Tada, Yoshiteru AU - Tada Y AD - Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan. FAU - Miyamoto, Takeshi AU - Miyamoto T AD - Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan. FAU - Shimada, Kenji AU - Shimada K AD - Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan. FAU - Matsushita, Nobuhisa AU - Matsushita N AD - Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan. FAU - Kanematsu, Yasuhisa AU - Kanematsu Y AD - Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan. FAU - Satomi, Junichiro AU - Satomi J AD - Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan. FAU - Hashimoto, Tomoki AU - Hashimoto T AD - Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA. FAU - Nagahiro, Shinji AU - Nagahiro S AD - Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan. LA - eng GR - R01 NS055876/NS/NINDS NIH HHS/United States GR - R01 NS082280/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160627 PL - England TA - J Neuroinflammation JT - Journal of neuroinflammation JID - 101222974 RN - 0 (Cytokines) RN - 0 (Timp1 protein, mouse) RN - 0 (Tissue Inhibitor of Metalloproteinase-1) RN - 12001-76-2 (Vitamin B Complex) RN - 127497-59-0 (Tissue Inhibitor of Metalloproteinase-2) RN - 935E97BOY8 (Folic Acid) RN - AE28F7PNPL (Methionine) RN - EC 1.6.3.- (NADPH Oxidase 4) RN - EC 1.6.3.- (NADPH Oxidases) RN - EC 1.6.3.- (Nox4 protein, mouse) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) RN - K848JZ4886 (Cysteine) SB - IM MH - *Aneurysm, Ruptured/complications/etiology/pathology/prevention & control MH - Animals MH - Arteries/pathology/ultrastructure MH - Blood Pressure/drug effects MH - Cysteine/blood MH - Cytokines/genetics/metabolism MH - Disease Models, Animal MH - Female MH - Folic Acid/*therapeutic use MH - Hyperhomocysteinemia/*chemically induced/physiopathology MH - Matrix Metalloproteinase 9/metabolism MH - Methionine/*toxicity MH - NADPH Oxidase 4 MH - NADPH Oxidases/metabolism MH - Ovariectomy MH - Rats MH - Rats, Sprague-Dawley MH - Subarachnoid Hemorrhage/etiology MH - Tissue Inhibitor of Metalloproteinase-1/metabolism MH - Tissue Inhibitor of Metalloproteinase-2/metabolism MH - Vitamin B Complex/*therapeutic use PMC - PMC4924228 OTO - NOTNLM OT - Anterior communicating artery OT - Cerebral aneurysm rupture OT - Folic acid OT - Hyperhomocysteinemia OT - Macrophage OT - Matrix metalloproteinase-9 OT - Methionine OT - Tissue inhibitor of metalloproteinase-2 EDAT- 2016/06/29 06:00 MHDA- 2017/10/11 06:00 PMCR- 2016/06/27 CRDT- 2016/06/29 06:00 PHST- 2015/12/10 00:00 [received] PHST- 2016/06/21 00:00 [accepted] PHST- 2016/06/29 06:00 [entrez] PHST- 2016/06/29 06:00 [pubmed] PHST- 2017/10/11 06:00 [medline] PHST- 2016/06/27 00:00 [pmc-release] AID - 10.1186/s12974-016-0634-3 [pii] AID - 634 [pii] AID - 10.1186/s12974-016-0634-3 [doi] PST - epublish SO - J Neuroinflammation. 2016 Jun 27;13(1):165. doi: 10.1186/s12974-016-0634-3.