Oxidative stress activates protein tyrosine kinase and matrix metalloproteinases leading to blood-brain barrier dysfunction
Oxidative stress activates protein tyrosine kinase and matrix metalloproteinases leading to blood-brain barrier dysfunction
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DOI：
10.1111/j.1471-4159.2006.04393.x
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发表时间：
2007-04-01
影响因子：
4.7
通讯作者：
Persidsky, Yuri
中科院分区：
文献类型：
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作者：
Haorah, James;Ramirez, Servio H.;Persidsky, Yuri
脑微血管内皮细胞(BMVEC)形成的血脑屏障(BBB)调节分子和白细胞进出脑的通道。氧化应激是神经退行性和神经炎性疾病以及与之相关的血脑屏障损伤的主要潜在原因。利用生长在基膜(BM)基质覆盖的多孔膜上的人BMVEC(BBB模型)，我们证明了活性氧物种(ROS)增加了BBB的通透性和单核细胞的迁移。ROS以蛋白酪氨酸激酶(PTK)依赖的方式激活基质金属蛋白酶(MMP1、MMP2和MMP9)，并降低MMPs的组织抑制物(TIMP-1和TIMP-2)。MMPs和PTK活性的增加与BM蛋白的降解和紧密连接(TJ)蛋白的酪氨酸磷酸化增强平行。这些效应和增加的通透性/单核细胞迁移可被MMPs、PTKs或抗氧化剂的抑制剂阻止，这表明氧化应激通过活化的MMPs降解BM蛋白和PTK介导的TJ蛋白磷酸化导致BBB损伤。这些发现表明，新的治疗干预措施可以改善中风或神经炎症等神经系统疾病的血脑屏障功能障碍。
The blood-brain barrier (BBB) formed by brain microvascular endothelial cells (BMVEC) regulates the passage of molecules and leukocytes in and out of the brain. Oxidative stress is a major underlying cause of neurodegenerative and neuroinflammatory disorders and BBB injury associated with them. Using human BMVEC grown on porous membranes covered with basement membrane (BM) matrix (BBB models), we demonstrated that reactive oxygen species (ROS) augmented permeability and monocyte migration across BBB. ROS activated matrix metalloproteinases (MMP-1, -2, and -9) and decreased tissue inhibitors of MMPs (TIMP-1 and -2) in a protein tyrosine kinase (PTK)-dependent manner. Increase in MMPs and PTK activities paralleled degradation of BM protein and enhanced tyrosine phosphorylation of tight junction (TJ) protein. These effects and enhanced permeability/monocyte migration were prevented by inhibitors of MMPs, PTKs, or antioxidant suggesting that oxidative stress caused BBB injury via degradation of BM protein by activated MMPs and by PTK-mediated TJ protein phosphorylation. These findings point to new therapeutic interventions ameliorating BBB dysfunction in neurological disorders such as stroke or neuroinflammation.