The lipid peroxidation product 4-hydroxy-2,3-nonenal increases AP-1-binding activity through caspase activation in neurons
The lipid peroxidation product 4-hydroxy-2,3-nonenal increases AP-1-binding activity through caspase activation in neurons
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DOI：
10.1046/j.1471-4159.2000.0740159.x
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发表时间：
2000-01-01
影响因子：
4.7
通讯作者：
Mattson, MP
中科院分区：
文献类型：
--
作者：
Camandola, S;Poli, G;Mattson, MP
转录因子激活蛋白-1（AP-1）响应神经元回路中的生理活动以及与各种急性和慢性神经退行性疾病相关的神经元损伤而被激活。膜脂质过氧化产物4-羟基-2，3-壬烯醛（HNE）越来越多地参与神经元兴奋性毒性和凋亡的各种范例中发生的神经元钙稳态的破坏。神经元凋亡过程中脂质过氧化和基因转录改变之间可能存在的机制联系尚未被研究。我们现在报告，暴露于培养的大鼠皮层神经元的HNE的凋亡浓度的结果在AP-I DNA结合活性的大幅增加。蛋白质合成抑制剂放线菌酮阻断了AP-1的诱导，这与诱导AP-1家族成员表达的要求一致。广谱半胱天冬酶抑制剂N-苄氧羰基-Val-Ala-Asp-氟甲基酮和半胱天冬酶-3抑制剂N-乙酰基-Asp-Glu-Val-Asp-醛阻断HNE诱导的AP-1 DNA结合活性的增加，证明AP-1活化中需要半胱天冬酶活化，HNE诱导c-Jun N-末端激酶（JNK）磷酸化，这被半胱天冬酶抑制剂阻止，表明HNE在JNK磷酸化处或上游起作用。细胞内钙螯合剂BAPTA-乙酰氧基甲酯完全阻止HNE刺激AP-1 DNA结合，表明需要钙。此外，抑制线粒体钙摄取（钌红）和膜通透性转换（环孢菌素A）的代理人衰减AP-1激活HNE，提示线粒体改变AP-1激活的贡献，总的来说，我们的数据表明，HNE破坏神经元钙稳态和扰乱线粒体功能，导致半胱天冬酶激活的情况。活化的半胱天冬酶反过来诱导JNK的活化，导致刺激AP-1 DNA结合蛋白的产生。HNE诱导的这一转录途径可能调节细胞死亡过程。
The transcription factor activator protein-1 (AP-1) is activated in response to physiological activity in neuronal circuits and in response to neuronal injury associated with various acute and chronic neurodegenerative conditions. The membrane lipid peroxidation product 4-hydroxy-2,3-nonenal (HNE) is increasingly implicated in the disruption of neuronal calcium homeostasis that occurs in various paradigms of neuronal excitotoxicity and apoptosis. The possible mechanistic links between lipid peroxidation and alterations in gene transcription during neuronal apoptosis have not previously been examined. We now report that exposure of cultured rat cortical neurons to an apoptotic concentration of HNE results in a large increase in AP-I DNA-binding activity. The protein synthesis inhibitor cycloheximide blocked the induction of AP-1, consistent with a requirement for induction of expression of AP-I family members. The broad-spectrum caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone and the caspase-3 inhibitor N-acetyl-Asp-Glu-Val-Asp-aldehyde blocked HNE-induced increases in AP-I DNA-binding activity, demonstrating a requirement for caspase activation in the activation of AP-1, HNE induced phosphorylation of c-Jun N-terminal kinase (JNK), which was prevented by caspase inhibitors, indicating that HNE was acting at or upstream of JNK phosphorylation. The intracellular calcium chelator BAPTA-acetoxymethyl ester completely prevented stimulation of AP-1 DNA-binding by HNE, indicating a requirement for calcium. Moreover, agents that suppress mitochondrial calcium uptake (ruthenium red) and membrane permeability transition (cyclosporin A) attenuated AP-1 activation by HNE, suggesting a contribution of mitochondrial alterations to AP-I activation, Collectively, our data suggest a scenario in which HNE disrupts neuronal calcium homeostasis and perturbs mitochondrial function, resulting in caspase activation. Activated caspases, in turn, induce activation of JNK, resulting in stimulation of AP-I DNA-binding protein production. This transcriptional pathway induced by HNE may modulate the cell death process.