Caspase-3 and the regulation of hypoxic neuronal death by vascular endothelial growth factor
Caspase-3 and the regulation of hypoxic neuronal death by vascular endothelial growth factor
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DOI：
10.1016/s0306-4522(01)00154-3
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发表时间：
2001-01-01
期刊：
影响因子：
3.3
通讯作者：
Greenberg, DA
中科院分区：
文献类型：
--
作者：
Jin, K;Mao, XO;Greenberg, DA
血管内皮生长因子（VEGF）具有神经营养和神经保护以及血管生成的特性，但参与VEGF介导的神经元存活的途径尚未确定。我们先前发现VEGF通过激活VEGF-2/胎肝激酶-1受体，磷脂酰肌醇3 ' -激酶，保护培养的神经细胞免于由血清戒断或缺氧诱导的死亡。Akt和核因子-κ B。我们现在报告，在小鼠皮质神经元培养缺氧，VEGF的神经保护作用涉及抑制细胞死亡途径介导的半胱天冬酶-3。暴露于缺氧24小时导致71 +/- 4%的培养神经元死亡; VEGF将其降低至40 +/- 1%（n = 3，P < 0.005），caspase-3抑制剂苄氧基羰基-DEVD-氟甲基酮将其降低至44 +/- 1%（n = 3，P < 0.005）。VEGF抑制半胱天冬酶-3的活化，如通过17-20-kDa半胱天冬酶-3切割产物所测量的，并且VEGF和活化的半胱天冬酶-3的免疫定位显示在单独的神经元群体中分离表达。针对VEGF的反义而非正义寡脱氧核苷酸增加表达活化的半胱天冬酶-3的神经元的比例，并相应地将缺氧神经元的活力降低了37 +/- 2%结果表明，VEGF通过抑制caspase-3的活化，并因此可作为脑缺血的内源性神经保护因子。(C)2001年IBRO。由爱思唯尔科技有限公司出版。保留所有权利。
Vascular endothelial growth factor (VEGF) has neurotrophic and neuroprotective as well as angiogenic properties, but the pathways involved in VEGF-mediated neuronal survival have not been identified. We found previously that VEGF protects cultured neural cells from death induced by serum withdrawal or hypoxia via the activation of VEGF-2/fetal liver kinase-1 receptors, phosphatidylinositol 3 ' -kinase. Akt and nuclear factor-kappaB. We now report that in mouse cortical neuron cultures subjected to hypoxia, the neuroprotective effect of VEGF involves suppression of cell-death pathways mediated by caspase-3. Exposure to hypoxia for 24 h caused the death of 71 +/- 4% of cultured neurons; this was reduced to 40 +/- 1% by VEGF (n = 3, P < 0.005) and to 44 +/- 1% by the caspase-3 inhibitor benzyloxycarbonyl-DEVD-fluoromethyl ketone (n = 3, P < 0.005). VEGF inhibited the activation of caspase-3 as measured by the 17-20-kDa caspase-3 cleavage product, and immunolocalization of VEGF and activated caspase-3 showed segregated expression in separate neuronal populations, An antisense, but not sense, oligodeoxyribonucleotide directed against VEGF increased the proportion of neurons expressing activated caspase-3, and correspondingly reduced the viability of hypoxic neurons by 37 +/- 2% (n = 3, P < 0.005).These findings suggest that VEGF protects neurons from hypoxic injury by inhibiting the activation of caspase-3, and could therefore act as an endogenous neuroprotective factor in cerebral ischemia. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved.