Intracerebroventricular Administration of an Endothelin ETB-Receptor Agonist Increases Expression of Matrix Metalloproteinase-2 and -9 in Rat Brain
Intracerebroventricular Administration of an Endothelin ETB-Receptor Agonist Increases Expression of Matrix Metalloproteinase-2 and -9 in Rat Brain
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DOI：
10.1254/jphs.10195fp
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发表时间：
2010-12-01
影响因子：
3.5
通讯作者：
Tanaka, Kazuhiro
中科院分区：
文献类型：
--
作者：
Koyama, Yutaka;Tanaka, Kazuhiro
基质金属蛋白酶（MMPs）是一类锌内肽酶，在脑损伤的病理生理反应中起着关键作用，MMPs在脑病理中上调，为了阐明脑MMP产生的细胞外信号，内皮素（ETs）是一类血管收缩肽，我们在脑室内给药500 pmol/天，检测了内皮素（ETs）的作用。增加大鼠海马和大脑中MMP2和MMP9的mRNA (1 3 11 15)-ET-1不影响mmp1、12和14的mRNA水平，Ala(1 3 11 15)-ET-1给药7天也增加了大脑中MMP2和MMP9的蛋白含量和蛋白水解活性。免疫组织化学观察显示，et灌胃大鼠海马和大脑中的星形胶质细胞具有MMP2和MMP9的反应。Ala(1 3 11 15)-ET-1 （100 nM）和ET-1 （100 nM）增加MMP2和MMP9 mrna， ET-1刺激培养星形胶质细胞中MMP2和MMP9蛋白的释放和蛋白水解活性，ETB拮抗剂BQ788抑制ET-1对星形胶质细胞MMP2和MMP9的作用，et诱导的MMP9表达被二硫代氨基甲酸吡啶蛋白酶体抑制剂I抑制，而MMP2不受et的抑制。这些结果表明，ET通过ETB受体刺激星形胶质细胞MMP2和MMP9的产生
Matrix metalloproteinases (MMPs), a family of zinc-endopeptidases, have a critical role in the pathophysiological responses in damaged brains MMPs are up-regulated in brain pathologies To clarify the extracellular signals involved in brain MMP production, the effects of endothelins (ETs), a family of vasoconstricting peptides, were examined Intracerebroventricular administration of 500 pmol/day Ala(1 3 11 15)-ET-1, an ETB-receptor agonist, increased the mRNAs of MMP2 and MMP9 in rat hippocampus and cerebrum Ala(1 3 11 15)-ET-1 did not affect mRNA levels of MMP 1, 12, and 14 Administration of Ala(1 3 11 15)-ET-1 for 7 days also increased the protein content and proteolytic activities of MMP2 and MMP9 in the cerebrum Immunohistochemical observations showed that astrocytes in the hippocampus and the cerebrum of ET-infused rats had MMP2 and MMP9 reactivities In rat cultured astrocytes, both Ala(1 3 11 15)-ET-1 (100 nM) and ET-1 (100 nM) Increased MMP2 and MMP9 mRNAs ET-1 stimulated the protein releases and the proteolytic activities of MMP2 and MMP9 from cultured astrocytes BQ788, an ETB antagonist, inhibited the effects of ET-1 on astrocytic MMP2 and MMP9 The ET-induced expression of MMP9, but not MMP2, was inhibited by pyrrolidine dithiocarbamate, proteasome inhibitor I, and MG132 These results suggest that ET stimulates astrocytic MMP2 and MMP9 production through ETB receptors