Korai Masaaki, Kitazato Keiko T, Tada Yoshiteru, Miyamoto Takeshi, Shimada Kenji, Matsushita Nobuhisa, Kanematsu Yasuhisa, Satomi Junichiro, Hashimoto Tomoki, Nagahiro Shinji
Department of Neurosurgery, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA.
J Neuroinflammation. 2016 Jun 27;13(1):165. doi: 10.1186/s12974-016-0634-3.
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.
高同型半胱氨酸血症（HHcy）与炎症以及血管壁中基质金属蛋白酶-9（MMP-9）表达增加有关。然而，HHcy在脑动脉瘤生长和破裂中的作用仍不清楚。
13周龄雌性Sprague-Dawley大鼠接受双侧卵巢切除术和右侧颈总动脉结扎，并给予8%高盐饮食以诱导脑动脉瘤形成。两周后，对其进行双侧后肾动脉结扎。将它们分为两组，一组在饮用水中添加蛋氨酸（MET），另一组不添加。在另一组实验中，评估了叶酸（FA）对脑动脉瘤的作用。
在12周的观察期内，在前交通动脉（AcomA）或Willis环后半部观察到因动脉瘤破裂导致的蛛网膜下腔出血。过量摄入MET诱导的HHcy显著增加了6 - 8周时动脉瘤破裂的发生率。在接受MET治疗的大鼠的AcomA处，我们观察到动脉瘤生长的促进以及M1巨噬细胞的浸润。此外，这些大鼠中MMP-9的mRNA水平、MMP-9与金属蛋白酶组织抑制剂-2的比值以及白细胞介素-6水平更高。FA治疗消除了MET的作用，表明AcomA处的炎症反应和血管降解归因于过量摄入MET导致的HHcy。
我们首次证明，在高血压去卵巢大鼠中，过量摄入MET诱导的HHcy可能与动脉瘤壁破裂倾向有关。
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