Blockade of Apoptosis Signal-Regulating Kinase 1 Attenuates Matrix Metalloproteinase 9 Activity in Brain Endothelial Cells and the Subsequent Apoptosis in Neurons after Ischemic Injury.
Blockade of Apoptosis Signal-Regulating Kinase 1 Attenuates Matrix Metalloproteinase 9 Activity in Brain Endothelial Cells and the Subsequent Apoptosis in Neurons after Ischemic Injury.
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DOI：
10.3389/fncel.2016.00213
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发表时间：
2016
影响因子：
5.3
通讯作者：
Koo BN
中科院分区：
文献类型：
--
作者：
Cheon SY;Cho KJ;Kim SY;Kam EH;Lee JE;Koo BN
氧化应激增加（包括脑缺血）可通过基质金属蛋白酶（MMP）导致血脑屏障功能障碍。已知MMP-9尤其是从脑内皮细胞释放的，参与脑缺血后发生的神经元细胞死亡。在细胞内信号网络中，凋亡信号调节激酶 1 (ASK1) 是氧化应激的主要激活剂，而氧化应激是脑缺血发病机制的一部分。 ASK1 还可促进缺血后细胞凋亡和脑梗塞，并与血管通透性和脑水肿的形成有关。然而，脑缺血后ASK1与MMP-9之间的关系仍不清楚。因此，本研究的目的是确定阻断 ASK1 是否会影响缺血脑和培养脑内皮细胞中 MMP-9 的活性。我们的结果表明，ASK1 抑制可有效降低体内和体外 MMP-9 活性。在内皮细胞培养物中，缺氧/再灌注后，ASK1 抑制上调磷脂酰肌醇 3-激酶/Akt/核因子红细胞 2 [NF-E2] 相关因子 2/血红素加氧酶-1 信号，并下调环氧合酶-2 信号。此外，在神经细胞培养物中，当神经元与从缺氧/再灌注组获得的内皮细胞条件培养基（EC-CM）一起孵育时，会发生细胞死亡。然而，在与 EC-CM 孵育并用 ASK1 抑制剂 NQDI-1 处理后，神经元细胞死亡有效减少。我们得出的结论是，抑制 ASK1 会降低脑内皮细胞中 MMP-9 的活性，并导致缺血性损伤后神经元细胞死亡减少。
Conditions of increased oxidative stress including cerebral ischemia can lead to blood–brain barrier dysfunction via matrix metalloproteinase (MMP). It is known that MMP-9 in particular is released from brain endothelial cells is involved in the neuronal cell death that occurs after cerebral ischemia. In the intracellular signaling network, apoptosis signal-regulating kinase 1 (ASK1) is the main activator of the oxidative stress that is part of the pathogenesis of cerebral ischemia. ASK1 also promotes apoptotic cell death and brain infarction after ischemia and is associated with vascular permeability and the formation of brain edema. However, the relationship between ASK1 and MMP-9 after cerebral ischemia remains unknown. Therefore, the aim of the present study was to determine whether blocking ASK1 would affect MMP-9 activity in the ischemic brain and cultured brain endothelial cells. Our results showed that ASK1 inhibition efficiently reduced MMP-9 activity in vivo and in vitro. In endothelial cell cultures, ASK1 inhibition upregulated phosphatidylinositol 3-kinase/Akt/nuclear factor erythroid 2 [NF-E2]-related factor 2/heme oxygenase-1 signals and downregulated cyclooxygenase-2 signals after hypoxia/reperfusion. Additionally, in neuronal cell cultures, cell death occurred when neurons were incubated with endothelial cell-conditioned medium (EC-CM) obtained from the hypoxia/reperfusion group. However, after incubation with EC-CM and following treatment with the ASK1 inhibitor NQDI-1, neuronal cell death was efficiently decreased. We conclude that suppressing ASK1 decreases MMP-9 activity in brain endothelial cells, and leads to decreased neuronal cell death after ischemic injury.
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影响因子：
1.3
作者：
Minh-Uyen Dao Thi;Trocme, Candice;Tracqui, Philippe
通讯作者：
Tracqui, Philippe
影响因子：
4.8
作者：
Ejima, K;Layne, MD;Perrella, MA
通讯作者：
Perrella, MA
影响因子：
2.2
作者：
Cheon, So Yeong;Cho, Kyoung Joo;Kim, Gyung Whan
通讯作者：
Kim, Gyung Whan
影响因子：
3.3
作者：
Meng, X.;Wang, M.;Sun, X.
通讯作者：
Sun, X.
DOI：
10.1097/01.wcb.0000122747.72175.47
发表时间：
2004-07-01
影响因子：
6.3
作者：
Lee, SR;Lo, EH
通讯作者：
Lo, EH