Heme-hemopexin complex attenuates neuronal cell death and stroke damage.
Heme-hemopexin complex attenuates neuronal cell death and stroke damage.
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DOI：
10.1038/jcbfm.2009.19
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发表时间：
2009-05
期刊：
影响因子：
--
通讯作者：
Doré S
中科院分区：
文献类型：
--
作者：
Li RC;Saleem S;Zhen G;Cao W;Zhuang H;Lee J;Smith A;Altruda F;Tolosano E;Doré S
血红素蛋白在缺氧/缺血条件下会发生降解，但释放的促氧化剂游离血红素无法回收，必须被降解。细胞外血红素与其高亲和力结合蛋白血红素 (HPX) 结合。此处显示血红素结合蛋白由皮质神经元表达，存在于小鼠小脑、皮质、海马和纹状体中。使用短暂性缺血模型（大脑中动脉闭塞 90 分钟，然后存活 96 小时），我们提供了 HPX 对大脑具有保护作用的证据，因为 HPX−/− 中的神经功能缺陷和梗塞体积显着大于野生型小鼠。针对潜在的保护性 HPX 细胞途径，我们观察到外源游离血红素降低了原代小鼠皮质神经元培养物中的细胞存活率，而与 HPX 结合的血红素没有毒性。血红素-HPX 复合物诱导 HO1，从而保护原代神经元免受血红素和促氧化剂叔丁基过氧化氢的毒性；在 HO1−/− 神经元培养物中，这种保护作用减弱。总而言之，这些数据表明 HPX 可以防止血红素诱导的毒性和氧化应激，并且 HO1 是必需的。我们建议血红素-HPX 系统通过保持游离血红素和结合血红素之间的紧密平衡来防止中风相关的损伤。因此，调节细胞外游离血红素水平（例如使用 HPX）可能具有神经保护作用。
Hemoproteins undergo degradation during hypoxic/ischemic conditions, but the pro-oxidant free heme that is released cannot be recycled and must be degraded. The extracellular heme associates with its high-affinity binding protein, hemopexin (HPX). Hemopexin is shown here to be expressed by cortical neurons and it is present in mouse cerebellum, cortex, hippocampus, and striatum. Using the transient ischemia model (90-min middle cerebral artery occlusion followed by 96-h survival), we provide evidence that HPX is protective in the brain, as neurologic deficits and infarct volumes were significantly greater in HPX−/− than in wild-type mice. Addressing the potential protective HPX cellular pathway, we observed that exogenous free heme decreased cell survival in primary mouse cortical neuron cultures, whereas the heme bound to HPX was not toxic. Heme–HPX complexes induce HO1 and, consequently, protect primary neurons against the toxicity of both heme and prooxidant tert-butyl hydroperoxide; such protection was decreased in HO1−/− neuronal cultures. Taken together, these data show that HPX protects against heme-induced toxicity and oxidative stress and that HO1 is required. We propose that the heme–HPX system protects against stroke-related damage by maintaining a tight balance between free and bound heme. Thus, regulating extracellular free heme levels, such as with HPX, could be neuroprotective.
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