Central role of PKCδ in glycoxidation-dependent apoptosis of human neurons
Central role of PKCδ in glycoxidation-dependent apoptosis of human neurons
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DOI：
10.1016/j.freeradbiomed.2004.12.002
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发表时间：
2005-04-01
影响因子：
7.4
通讯作者：
Domenicotti, C
中科院分区：
文献类型：
--
作者：
Nitti, M;d'Abramo, C;Domenicotti, C
晚期糖基化终产物（AGEs）的积累诱导细胞内氧化还原平衡的改变，导致细胞功能损伤。目前文献报道，由AGEs与其特异性受体RAGEs相互作用触发的细胞内信号通路取决于细胞类型和激活/应激状态。在这项工作中，NT2人神经元暴露于含有750-3000 pmol/ml戊苷的糖化胎儿血清中48小时；当AGE浓度达到1500 pmol/ml时，细胞凋亡率随AGE浓度的增加呈线性增加，但当AGE浓度达到3000 pmol/ml时，细胞发生坏死性死亡。1500 pmol/ml浓度的戊sidine对细胞凋亡的影响最大（40%的凋亡神经元），能够决定细胞内活性氧的早期产生和RAGE水平的增加。在这些条件下，蛋白激酶C (PKC) 6的活性提高了约2倍，氧化还原敏感转录因子激活蛋白-1 （AP-1）的DNA结合活性提高了2.5倍。通过500 μ M维生素E、20 μ g/ml银杏叶提取物或3 μ M Rottlerin （PKC δ抑制剂）预处理神经元，证实了氧化应激、PKC δ活性、AP-1激活和细胞凋亡之间的关系；这些预处理能够保护神经元免受糖氧化依赖性的影响。(c) 2004 Elsevier Inc.版权所有。
Accumulation of advanced glycation end products (AGEs) induces alterations in the intracellular redox balance, leading cells to functional injury. Current literature reports that intracellular signaling triggered by the interaction of AGEs with their specific receptors RAGEs depends on the cell type and the state of activation/stress. In this work, NT2 human neurons were exposed for 48 h to glycated fetal serum containing 750-3000 pmol/ml pentosidine; the treatment induced an increase in apoptosis rate linear with AGE concentration up to 1500 pmol/ml, but necrotic death was elicited with the highest AGE amount employed (3000 pmol/ml pentosidine). Pentosidine at 1500 pmol/ml, which was the concentration responsible for the highest apoptotic effect (40% of apoptotic neurons), was able to determine early generation of intracellular reactive oxygen species and increase in RAGE levels. Under these conditions, protein kinase C (PKC) 6 activity was increased approximately 2-fold, and DNA binding activity of redox-sensitive transcription factor activator protem-1 (AP-1) was enhanced 2.5-fold. A relationship among oxidative stress, PKC delta activity, AP-1 activation, and apoptosis was demonstrated by pretreating neurons with 500 mu M vitamin E, with 20 mu g/ml Ginkgo biloba extract, or with 3 mu M Rottlerin, inhibitor of PKC delta; these pretreatments were able to protect neurons from the glycoxidation-dependent effects. (c) 2004 Elsevier Inc. All rights reserved.