title: Hyperhomocysteinemia induced by excessive methionine intake promotes rupture of cerebral aneurysms in ovariectomized rats.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan. komakun@gmail.com.|Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA. komakun@gmail.com.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Korai
authors.affiliation: Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Keiko T
authors.initials: KT
authors.lastname: Kitazato
authors.affiliation: Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Tada
authors.affiliation: Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miyamoto
authors.affiliation: Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Shimada
authors.affiliation: Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Matsushita
authors.affiliation: Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Kanematsu
authors.affiliation: Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Junichiro
authors.initials: J
authors.lastname: Satomi
authors.affiliation: Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Hashimoto
authors.affiliation: Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Nagahiro
mesh_terms: D017542:Aneurysm, Ruptured / Q000150:complications / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D001158:Arteries / Q000473:pathology / Q000648:ultrastructure; D001794:Blood Pressure / Q000187:drug effects; D003545:Cysteine / Q000097:blood; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005492:Folic Acid / Q000627:therapeutic use*; D020138:Hyperhomocysteinemia / Q000139:chemically induced* / Q000503:physiopathology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008715:Methionine / Q000633:toxicity*; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013345:Subarachnoid Hemorrhage / Q000209:etiology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D014803:Vitamin B Complex / Q000627:therapeutic use*
chemical_list: D016207:Cytokines; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D014803:Vitamin B Complex; D019716:Tissue Inhibitor of Metalloproteinase-2; D005492:Folic Acid; D008715:Methionine; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; D020780:Matrix Metalloproteinase 9; D003545:Cysteine
keywords: Anterior communicating artery; Cerebral aneurysm rupture; Folic acid; Hyperhomocysteinemia; Macrophage; Matrix metalloproteinase-9; Methionine; Tissue inhibitor of metalloproteinase-2