Enhanced cerebrovascular expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 via the MEK/ERK pathway during cerebral ischemia in the rat.
Enhanced cerebrovascular expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 via the MEK/ERK pathway during cerebral ischemia in the rat.
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DOI：
10.1186/1471-2202-10-56
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发表时间：
2009-06-04
期刊：
影响因子：
2.4
通讯作者：
Edvinsson L
中科院分区：
文献类型：
--
作者：
Maddahi A;Chen Q;Edvinsson L
脑缺血的特征通常是局部血流和代谢的减少以及梗塞区域血脑屏障的破坏。脑卒中后水肿的形成和血脑屏障的开放与基质金属蛋白酶-9（MMP-9）和基质金属蛋白酶组织抑制剂-1（TIMP-1）的表达增强有关。在此，我们发现大鼠大脑中动脉闭塞（MCAO）2小时后的梗死体积为24.8 ± 2%，神经功能降低，随后再循环48小时。免疫细胞化学和共聚焦显微镜显示缺血MCA和相关脑内微血管平滑肌细胞中MMP-9、TIMP-1和磷酸化ERK 1/2的表达增强。MEK 1/2特异性抑制剂U 0126在缺血后0小时或6小时腹腔内给药，可显著缩小梗死体积（分别为11.8 ± 2%和14.6 ± 3%; P < 0.05），改善神经功能，使磷酸化ERK 1/2的表达正常化，并降低血管壁MMP-9和TIMP-1的表达。MCAO后12小时给予U 0126并没有改变MMP-9的表达。免疫细胞化学显示MMP-9/TIMP-1和星形胶质细胞/胶质细胞标记物GFAP在血管壁中的表达没有重叠。这些数据首次表明，与局灶性缺血后血脑屏障破坏相关的MMP-9和TIMP-1的血管表达升高通过MEK/ERK途径进行转录调节。
Cerebral ischemia is usually characterized by a reduction in local blood flow and metabolism and by disruption of the blood-brain barrier in the infarct region. The formation of oedema and opening of the blood-brain barrier in stroke is associated with enhanced expression of metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1). Here, we found an infarct volume of 24.8 ± 2% and a reduced neurological function after two hours of middle cerebral artery occlusion (MCAO), followed by 48 hours of recirculation in rat. Immunocytochemistry and confocal microscopy revealed enhanced expression of MMP-9, TIMP-1, and phosphorylated ERK1/2 in the smooth muscle cells of the ischemic MCA and associated intracerebral microvessels. The specific MEK1/2 inhibitor U0126, given intraperitoneal zero or 6 hours after the ischemic event, reduced the infarct volume significantly (11.8 ± 2% and 14.6 ± 3%, respectively; P < 0.05), improved neurological function, normalized expression of phosphorylated ERK1/2, and reduced expression of MMP-9 and TIMP-1 in the vessel walls. Administration of U0126 12 hours after MCAO did not alter the expression of MMP-9. Immunocytochemistry showed no overlap in expression between MMP-9/TIMP-1 and the astrocyte/glial cell marker GFAP in the vessel walls. These data are the first to show that the elevated vascular expression of MMP-9 and TIMP-1, associated with breakdown of the blood-brain barrier following focal ischemia, are transcriptionally regulated via the MEK/ERK pathway.
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影响因子：
4.8
作者：
MENZIES, SA;SMITH, RR;BETZ, AL
通讯作者：
BETZ, AL
DOI：
10.1152/ajpheart.00857.2007
发表时间：
2007-12-01
影响因子：
4.8
作者：
Ansar, Saema;Vikman, Petter;Edvinsson, Lars
通讯作者：
Edvinsson, Lars
影响因子：
8.3
作者：
Stenman, E;Malmsjo, M;Edvinsson, L
通讯作者：
Edvinsson, L
影响因子：
2
作者：
Henriksson, Marie;Stenman, Emelie;Edvinsson, Lars
通讯作者：
Edvinsson, Lars
影响因子：
2.4
作者：
Maddahi, Aida;Edvinsson, Lars
通讯作者：
Edvinsson, Lars