Mechanisms of neuroprotection by hemopexin: modeling the control of heme and iron homeostasis in brain neurons in inflammatory states.
Mechanisms of neuroprotection by hemopexin: modeling the control of heme and iron homeostasis in brain neurons in inflammatory states.
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DOI：
10.1111/jnc.12165
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发表时间：
2013-04
影响因子：
4.7
通讯作者：
Smith A
中科院分区：
文献类型：
--
作者：
Hahl P;Davis T;Washburn C;Rogers JT;Smith A
Hemopexin在中风和脑内出血的小鼠模型中提供神经保护，并通过血红素加氧酶-1（HO 1）活性在体外保护神经元免受血红素或活性氧（ROS）毒性。为了模拟人脑神经元经历血管扩张和炎症，我们使用人神经母细胞瘤细胞，血红素血红素结合蛋白复合物，和生理相关的ROS，例如，H2 O2和HOCl，提供新的见解的潜在机制，从而血红素结合蛋白安全地维持血红素和铁稳态。人淀粉样前体蛋白（hAPP），需要从神经元的铁输出，诱导约两倍后，血红素血红素结合蛋白内吞铁从血红素catalysts通过hAPP mRNA的铁调节元件。血红素-血红素结合蛋白对ROS的损伤具有相对抗性，并且在暴露于叔丁基过氧化氢后保留其诱导细胞保护性HO 1的能力，尽管通过体外暴露于高浓度的H2 O2，诱导受到损害，但未被消除。在非溶血状态下占主导地位的脱辅基血红素结合蛋白抵抗H2 O2和HOCl的损伤，除了可能在体内的最高浓度。血红素-白蛋白和白蛋白是ROS的优先靶点;因此，白蛋白在生物流体如CSF和血浆中保护血红素结合蛋白，其中它是丰富的。这些观察结果提供了强有力的证据，证明血红素结合蛋白在创伤性脑损伤后具有神经保护作用，在CNS中释放血红素，以及在随后的炎症期间。Hemopexin螯合血红素，从而防止导致毒性的不受调节的血红素摄取;它安全地将血红素递送到神经元细胞;并且它激活包括HO 1和hAPP在内的蛋白质的诱导，这些蛋白质将血红素和铁保持在神经元中的安全水平。
Hemopexin provides neuroprotection in mouse models of stroke and intracerebral hemorrhage and protects neurons in vitro against heme or reactive oxygen species (ROS) toxicity via heme oxygenase-1 (HO1) activity. To model human brain neurons experiencing hemorrhages and inflammation, we used human neuroblastoma cells, heme–hemopexin complexes, and physiologically relevant ROS, for example, H2O2 and HOCl, to provide novel insights into the underlying mechanism whereby hemopexin safely maintains heme and iron homeostasis. Human amyloid precursor protein (hAPP), needed for iron export from neurons, is induced ~twofold after heme–hemopexin endocytosis by iron from heme catabolism via the iron-regulatory element of hAPP mRNA. Heme– hemopexin is relatively resistant to damage by ROS and retains its ability to induce the cytoprotective HO1 after exposure to tert-butylhydroperoxide, although induction is impaired, but not eliminated, by exposure to high concentrations of H2O2 in vitro. Apo-hemopexin, which predominates in non-hemolytic states, resists damage by H2O2 and HOCl, except for the highest concentrations likely in vivo. Heme– albumin and albumin are preferential targets for ROS; thus, albumin protects hemopexin in biological fluids like CSF and plasma where it is abundant. These observations provide strong evidence that hemopexin will be neuroprotective after traumatic brain injury, with heme release in the CNS, and during the ensuing inflammation. Hemopexin sequesters heme, thus preventing unregulated heme uptake that leads to toxicity; it safely delivers heme to neuronal cells; and it activates the induction of proteins including HO1 and hAPP that keep heme and iron at safe levels in neurons.
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影响因子：
64.5
作者：
Duce JA;Tsatsanis A;Cater MA;James SA;Robb E;Wikhe K;Leong SL;Perez K;Johanssen T;Greenough MA;Cho HH;Galatis D;Moir RD;Masters CL;McLean C;Tanzi RE;Cappai R;Barnham KJ;Ciccotosto GD;Rogers JT;Bush AI
通讯作者：
Bush AI
影响因子：
3.5
作者：
Flaherty, Meghan M.;Rish, Kimberley R.;Crumbliss, Alvin L.
通讯作者：
Crumbliss, Alvin L.
脑癌敲除小鼠中脑出血后纹状体损伤和行为缺陷增加。
影响因子：
4.1
作者：
Chen L;Zhang X;Chen-Roetling J;Regan RF
通讯作者：
Regan RF
影响因子：
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作者：
Gupta S;Ahern K;Nakhl F;Forte F
通讯作者：
Forte F
影响因子：
--
作者：
Bandyopadhyay, Sanghamitra;Ni, Jake;Rogers, Jack T.
通讯作者：
Rogers, Jack T.