Heme oxygenase-2 is neuroprotective in cerebral ischemia
Heme oxygenase-2 is neuroprotective in cerebral ischemia
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DOI：
10.1007/bf03401984
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发表时间：
1999-10-01
影响因子：
5.7
通讯作者：
Snyder, SH
中科院分区：
文献类型：
--
作者：
Doré, S;Sampei, K;Snyder, SH
血红素加氧酶（HO）被认为是神经系统中的一种有效的抗氧化酶;它将血红素从含血红素的蛋白质中降解，产生一氧化碳、铁和胆绿素，胆绿素迅速还原为胆红素。该酶的第一个鉴定的同种型，HO 1，是一种诱导性愈合休克蛋白，在外周器官中高水平表达，在正常条件下在大脑中几乎检测不到，而HO 2是组成性的，在大脑中最高度集中。有趣的是，虽然HO 2是组成型表达的，但其活性可通过磷酸化调节。我们证明了由HO 2形成的胆红素是神经保护剂，因为在HO 2靶向缺失（HO 2（-/-））小鼠的神经元培养物中神经毒性增强，并被低浓度的胆红素逆转。我们现在表明，大脑中动脉闭塞（MCAO）和再灌注后的神经损伤，血管性中风的局灶性缺血模型，在HO 2（-/-）动物中显著恶化。相比之下，HO 1（-/-）小鼠的中风损伤没有显著改变，尽管它们更虚弱。在HO 2（-/-）动物中，颅内注射N-甲基-D-天冬氨酸（NMDA）后的神经损伤也加重。这些发现确立了HO 2作为脑中的内源性神经保护系统，其药理学操作可能具有治疗相关性。
Heme oxygenase (HO) is believed to be a potent antioxidant enzyme in the nervous system; it degrades her-ne from heme-containing proteins, giving rise to carbon monoxide, iron, and biliverdin, which is rapidly reduced to bilirubin. The first identified isoform of the enzyme, HO1, is an inducible heal-shock protein expressed in high levels in peripheral organs and barely detectable under normal conditions in the brain, whereas HO2 is constitutive and most highly concentrated in the brain. interestingly, although HO2 is constitutively expressed, its activity can be modulated by phosphorylation. We demonstrated that bilirubin, formed from HO2, is neuroprotectant, as neurotoxicity is augmented in neuronal cultures from mice with targeted deletion of HO2 (HO2(-/-)) and reversed by low concentrations of bilirubin. We now show that neural damage following middle cerebral artery occlusion (MCAO) and reperfusion, a model of focal ischemia of vascular stroke, is substantially worsened in HO2(-/-) animals. By contrast, stroke damage is nor significantly altered in HO1(-/-) mice, despite their greater debility. Neural damage following intracranial injections of N-methyl-D-aspartate (NMDA) is also accentuated in HO2(-/-) animals. These findings establish HO2 as an endogenous neuroprotective system in the brain whose pharmacologic manipulation may have therapeutic relevance.