Preventing HIV-1 tat-induced neuronal apoptosis using antioxidant enzymes: Mechanistic and therapeutic implications
Preventing HIV-1 tat-induced neuronal apoptosis using antioxidant enzymes: Mechanistic and therapeutic implications
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DOI：
10.1016/j.virol.2007.02.004
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发表时间：
2007-07-05
期刊：
影响因子：
3.7
通讯作者：
Strayer, David S.
中科院分区：
文献类型：
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作者：
Agrawal, Lokesh;Louboutin, Jean-Pierre;Strayer, David S.
HIV-1蛋白，特别是gp 120和达特，可引起活性氧自由基（reactive oxygen species，ROS），引起神经元凋亡。我们使用抗氧化酶，铜/锌超氧化物歧化酶（SOD 1）和谷胱甘肽过氧化物酶（GPx 1），研究信号和神经保护从Tat诱导的细胞凋亡。SOD 1将超氧化物转化为过氧化物; GPx 1将过氧化物转化为水。用携带SOD 1和GPx 1的SV 40衍生载体转导原代人神经元，然后加入HIV-1达特蛋白。SV（SOD 1）和SV（GPx 1）都传递了大量的转基因表达。达特降低内源性细胞SOD 1和GPx 1，但不转导。达特使神经元[Ca（2+）]（i）迅速增加，而SV（SOD 1）或SV（GPx I）不改变这种作用。然而，两种载体一起阻断Tat诱导的[Ca 2 +]（i）通量。类似地，SV（SOD 1）和SV（GPx 1）都不能保护神经元免受Tat诱导的凋亡，但两种载体一起都可以。因此，达特激活多个信号通路，其中一个通路中超氧化物作为中间体，而另一个通路利用过氧化物。因此，保护神经元免受达特伤害的基因传递必须同时针对这两种物质。(C)2007爱思唯尔公司All rights reserved.
HIV-1 proteins, especial ly gp 120 and Tat, elicit reactive oxygen species (ROS) and cause neuron apoptosis. We used antioxidant enzymes, Cu/Zn superoxide dismutase (SOD1) and glutathione peroxidase (GPx1) to study signaling and neuroprotection from Tat-induced apoptosis. SOD1 converts superoxide to peroxide; GPx1 converts peroxide to water. Primary human neurons were transduced with SV40-derived vectors carrying SOD1 and GPx1, then HIV-1 Tat protein was added. Both SV(SOD 1) and SV(GPx1) delivered substantial transgene expression. Tat decreased endogenous cellular, but not transduced, SOD1 and GPx1. Tat rapidly increased neuron [Ca (2+)](i), which effect was not altered by SV(SOD 1) or SV (GPx I). However, both vectors together blocked Tat-induced [Ca2+](i) fluxes. Similarly, neither SV(SOD1) nor SV(GPx1) protected neurons from Tat-induced apoptosis, but both vectors together did. Tat therefore activates multiple signaling pathways, in one of which superoxide acts as an intermediate while the other utilizes peroxide. Gene delivery to protect neurons from Tat must therefore target both. (C) 2007 Elsevier Inc. All rights reserved.