Toxic effects of cobalt in primary cultures of mouse astrocytes -: Similarities with hypoxia and role of HIF-1α
Toxic effects of cobalt in primary cultures of mouse astrocytes -: Similarities with hypoxia and role of HIF-1α
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DOI：
10.1016/j.bcp.2006.11.008
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发表时间：
2007-03-01
影响因子：
5.8
通讯作者：
Dare, Elisabetta
中科院分区：
文献类型：
--
作者：
Karovic, Olga;Tonazzini, Ilaria;Dare, Elisabetta
钴被怀疑会导致人类的记忆障碍，并被报道在动物模型中引起神经毒性。我们研究了钴对原代培养的小鼠星形胶质细胞的影响。CoCl2(0.2-0.8 mM)可引起剂量依赖性的ATP耗竭、细胞凋亡(细胞萎缩、磷脂酰丝氨酸外化和染色质重排)和继发性坏死。线粒体似乎是钴中毒的主要靶点，表现为线粒体膜电位(Delta Psi M)的丧失和凋亡诱导因子(AIF)等致凋亡因子的释放。用bongkrekic酸预处理可减少线粒体通透性转换(MPT)孔对ATP的消耗。钴增加了氧自由基的产生，但抗氧化剂并不能防止毒性。对ATP刺激也有受损的反应，评估为细胞内钙的较低升高。与缺氧和二甲氧烯丙基甘氨酸(DMOG)类似，钴可以稳定缺氧诱导因子-1(HIF-1α)的α亚基。在这一早期事件之后，HIF-1调节的基因，如应激蛋白HO-1，促凋亡因子Nip3和iNOS的表达增加。虽然这三种刺激都激活了HIF-1α通路，降低了ATP水平，但下游作用不同。DMOG只抑制细胞增殖，而其他两种情况则通过细胞凋亡和坏死导致细胞死亡。这表明，钴和低氧不仅诱导HIF-1α调节的基因，而且还影响类似的其他细胞功能，包括新陈代谢。(C)2006 Elsevier Inc.保留所有权利。
Cobalt is suspected to cause memory deficit in humans and was reported to induce neurotoxicity in animal models. We have studied the effects of cobalt in primary cultures of mouse astrocytes. CoCl2 (0.2-0.8 mM) caused dose-dependent ATP depletion, apoptosis (cell shrinkage, phosphatidylserine externalization and chromatin rearrangements) and secondary necrosis. The mitochondria appeared to be a main target of cobalt toxicity, as shown by the loss of mitochondrial membrane potential (Delta Psi m) and release from the mitochondria of apoptogenic factors, e.g. apoptosis inducing factor (AIF). Pre-treatment with bongkrekic acid reduced ATP depletion, implicating the involvement of the mitochondrial permeability transition (MPT) pore. Cobalt increased the generation of oxygen radicals, but antioxidants did not prevent toxicity. There was also an impaired response to ATP stimulation, evaluated as a lower raise in intracellular calcium. Similarly to hypoxia and dymethyloxallyl glycine (DMOG), cobalt triggered stabilization of the alpha-subunit of hypoxia-inducible factor HIF-1 (HIF-1 alpha). This early event was followed by an increased expression of HIF-1 regulated genes, e.g. stress protein HO-1, pro-apoptotic factor Nip3 and iNOS. Although all of the three stimuli activated the HIF-1 alpha pathway and decreased ATP levels, the downstream effects were different. DMOG only inhibited cell proliferation, whereas the other two conditions caused cell death by apoptosis and necrosis. This points to cobalt and hypoxia not only inducing HIF-1 alpha regulated genes but also affecting similarly other cellular functions, including metabolism. (c) 2006 Elsevier Inc. All rights reserved.