Impact of Monocyte Chemoattractant Protein-1 Deficiency on Cerebral Aneurysm Formation
Impact of Monocyte Chemoattractant Protein-1 Deficiency on Cerebral Aneurysm Formation
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DOI：
10.1161/strokeaha.108.532556
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发表时间：
2009-03-01
期刊：
影响因子：
8.3
通讯作者：
Hashimoto, Nobuo
中科院分区：
文献类型：
--
作者：
Aoki, Tomohiro;Kataoka, Hiroharu;Hashimoto, Nobuo
背景和目的——最近的研究表明，慢性炎症积极参与脑动脉瘤（CA）的形成。巨噬细MCP-1(-/-)小鼠和编码MCP-1显性失活突变体(7ND)的质粒DNA检查了MCP-1在CA形成中的作用。采用免疫组织化学法检测人CA中MCP-1的表达。结果-CA形成早期动脉瘤壁中MCP-1表达上调。 MCP-1-/- 小鼠表现出 CA 形成和巨噬细胞积累显着减少，基质金属蛋白酶-2、-9 和诱导型一氧化氮合酶表达降低。核因子-κ B DNA 结合形式的免疫组织化学显示，在表达 MCP-1 的细胞中核因子-κ B 被激活。 7ND 阻断 MCP-1 活性可抑制大鼠 CA 进展。在人类CA中，MCP-1也在CA壁中表达。结论-这些数据表明MCP-1作为单核细胞/巨噬细胞的主要趋化剂在CA形成中发挥着至关重要的作用。 CA 壁中的 MCP-1 表达是通过核因子 kappa B 激活诱导的。 MCP-1可能是预防CA进展的药物治疗的新靶点。 （中风。2009 年；40：942-951。）
Background and Purpose-Recent studies have suggested that chronic inflammation actively participates in cerebral aneurysm ( CA) formation. Macrophages accumulate in CA walls and express proinflammatory genes promoting CA progression, but the molecular mechanisms of monocyte/macrophage recruitment into CA walls remain to be elucidated.Methods-Monocyte chemoattractant protein-1 (MCP-1) expression in experimentally induced CAs was assessed by immunohistochemistry and Western blotting. The role of MCP-1 in CA formation was examined by MCP-1(-/-) mice and a plasmid DNA encoding a dominant negative mutant of MCP-1 (7ND). MCP-1 expression in human CAs was examined by immunohistochemistry.Results-MCP-1 expression was upregulated in aneurysmal walls at the early stage of CA formation. MCP-1-/- mice exhibited a significant decrease of CA formation and macrophage accumulation with decreased expression of matrix metalloproteinase-2, -9 , and inducible nitric oxide synthase. Immunohistochemistry for the DNA binding form of nuclear factor-kappa B showed nuclear factor-kappa B activation in MCP-1-expressing cells. Blockade of MCP-1 activity by 7ND resulted in the inhibition of CA progression in rats. In human CAs, MCP-1 was also expressed in CA walls.Conclusions-These data suggest that MCP-1 plays a crucial role in CA formation as a major chemoattractant for monocyte/macrophage. MCP-1 expression in CA walls is induced through nuclear factor-kappa B activation. MCP-1 may be a novel therapeutic target of medical treatment preventing CA progression. (Stroke. 2009; 40:942-951.)