Hypoxia-inducible factor 1 protects hypoxic astrocytes against glutamate toxicity.
Hypoxia-inducible factor 1 protects hypoxic astrocytes against glutamate toxicity.
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DOI：
10.1042/an20120006
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发表时间：
2012-05-30
期刊：
影响因子：
4.7
通讯作者：
Shi H
中科院分区：
文献类型：
--
作者：
Badawi Y;Ramamoorthy P;Shi H
中风是一种主要的神经系统疾病，其特征是谷氨酸（谷氨酸）浓度增加，导致兴奋性毒性，最终导致大脑细胞损伤和死亡。HIF-1 （hypoxia-inducible factor-1）是一种转录因子，在促进细胞适应缺氧条件中起着重要的保护作用。已知HIF-1的可调节亚基HIF-1α在严重缺血时由星形胶质细胞表达。然而，HIF-1对缺血期间Glu毒性星形胶质细胞的影响尚未得到很好的研究。我们研究了HIF-1在保护缺血性星形胶质细胞免受Glu毒性的作用。GFAP（胶质原纤维酸性蛋白）免疫染色证实了在正常缺氧条件下1 mM Glu存在下星形胶质细胞的形态改变。有趣的是，当星形胶质细胞暴露于严重缺氧（0.1% O2）时，改变的细胞形态随着HIF-1α的上调而改善。为了确定HIF-1的保护作用，我们测试了两种HIF-1α抑制剂YC-1[3-（50-羟甲基-20-呋喃基）-1-苄基唑]和2Me2（2-甲氧基雌二醇）的作用。这两种抑制剂都降低了星形胶质细胞形态的恢复，增加了细胞死亡。鉴于缺血增加活性氧（ROS），我们研究了GSH（还原性谷胱甘肽）在这种保护机制中的作用。缺氧时GSH升高，这与星形胶质细胞中HIF-1α稳定化的增加有关。此外，BSO （l-丁硫酮亚砜胺）抑制GSH可降低HIF-1α的表达，提示其在稳定HIF-1α中的作用。总之，我们的研究结果表明，缺氧条件下HIF-1α的表达对星形胶质细胞在Glu毒性反应中维持细胞形态和活力具有保护作用。
Stroke is a major neurological disorder characterized by an increase in the Glu (glutamate) concentration resulting in excitotoxicity and eventually cellular damage and death in the brain. HIF-1 (hypoxia-inducible factor-1), a transcription factor, plays an important protective role in promoting cellular adaptation to hypoxic conditions. It is known that HIF-1α, the regulatable subunit of HIF-1, is expressed by astrocytes under severe ischaemia. However, the effect of HIF-1 on astrocytes following Glu toxicity during ischaemia has not been well studied. We investigated the role of HIF-1 in protecting ischaemic astrocytes against Glu toxicity. Immunostaining with GFAP (glial fibrillary acidic protein) confirmed the morphological modification of astrocytes in the presence of 1 mM Glu under normoxia. Interestingly, when the astrocytes were exposed to severe hypoxia (0.1% O2), the altered cell morphology was ameliorated with up-regulation of HIF-1α. To ascertain HIF-1's protective role, effects of two HIF-1α inhibitors, YC-1 [3-(50-hydroxymethyl-20-furyl)-1-benzylindazole] and 2Me2 (2-methoxyoestradiol), were tested. Both the inhibitors decreased the recovery in astrocyte morphology and increased cell death. Given that ischaemia increases ROS (reactive oxygen species), we examined the role of GSH (reduced glutathione) in the mechanism for this protection. GSH was increased under hypoxia, and this correlated with an increase in HIF-1α stabilization in the astrocytes. Furthermore, inhibition of GSH with BSO (l-butathione sulfoximine) decreased HIF-1α expression, suggesting its role in the stabilization of HIF-1α. Overall, our results indicate that the expression of HIF-1α under hypoxia has a protective effect on astrocytes in maintaining cell morphology and viability in response to Glu toxicity.