Mitigation of peroxynitrite-mediated nitric oxide (NO) toxicity as a mechanism of induced adaptive NO resistance in the CNS.
Mitigation of peroxynitrite-mediated nitric oxide (NO) toxicity as a mechanism of induced adaptive NO resistance in the CNS.
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DOI：
10.1111/j.1471-4159.2009.05884.x
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发表时间：
2009-04
影响因子：
4.7
通讯作者：
Estevez AG
中科院分区：
文献类型：
--
作者：
Bishop A;Gooch R;Eguchi A;Jeffrey S;Smallwood L;Anderson J;Estevez AG
在CNS损伤和疾病期间，NO以高通量速率释放，导致形成过氧亚硝酸盐（ONOO-）和其他反应性含氮物质（RNS），其硝酸化蛋白质的酪氨酸以形成3-硝基酪氨酸（3-NY），导致细胞死亡。以前，我们已经发现，运动神经元暴露于低水平的NO成为抵抗随后的细胞毒性NO的挑战，一种被称为诱导适应性阻力（IAR）的效果。在这里，我们报告IAR减轻，不仅细胞死亡，但3 NY形成响应细胞毒性NO。此外，NO清除剂之前NO挑战重复IAR，牵连RNS细胞死亡。在细胞毒性NO激发前添加尿酸（过氧亚硝酸根清除剂），重复IAR，暗示过氧亚硝酸根与随后的3-NY形成在细胞死亡中，并废除该途径作为IAR的机制。IAR依赖于血红素代谢酶血红素加氧酶-1（HO 1），如通过特定HO 1抑制剂消除IAR所示，以及通过发现从HO-1缺失小鼠中分离的神经元具有增加的NO敏感性以及伴随的增加的3-NY形成。这些数据表明，IAR是一种HO 1依赖性机制，可防止运动神经元中过氧亚硝酸盐介导的NO毒性，从而阐明缓解CNS疾病和损伤的治疗靶点。
During CNS injury and diseases, NO is released at a high flux rate leading to formation of peroxynitrite (ONOO-) and other reactive nitrogenous species (RNS), which nitrate tyrosines of proteins to form 3-nitrotyrosine (3-NY), leading to cell death. Previously, we have found that motor neurons exposed to low levels of NO become resistant to subsequent cytotoxic NO challenge; an effect dubbed induced adaptive resistance (IAR). Here we report IAR mitigates, not only cell death, but 3NY formation in response to cytotoxic NO. Addition of an NO scavenger before NO challenge duplicates IAR, implicating RNS in cell death. Addition of uric acid (a peroxynitrite scavenger) before cytotoxic NO challenge, duplicates IAR, implicating peroxynitrite, with subsequent 3-NY formation, in cell death, and abrogation of this pathway as a mechanism of IAR. IAR is dependent on the heme-metabolizing enzyme, heme oxygenase-1 (HO1), as indicated by the elimination of IAR by a specific HO1 inhibitor, and by the finding that neurons isolated from HO-1 null mice have increased NO sensitivity with concomitant increased 3-NY formation. This data indicates that IAR is an HO1-dependent mechanism that prevents peroxynitrite-mediated NO toxicity in motor neurons, thereby elucidating therapeutic targets for the mitigation of CNS disease and injury.
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DOI：
10.1073/pnas.062604199
发表时间：
2002-03-19
影响因子：
11.1
作者：
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通讯作者：
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DOI：
10.1016/j.bbrc.2004.10.010
发表时间：
2004-12-03
影响因子：
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影响因子：
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作者：
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Beckman, JS
DOI：
10.1161/01.atv.0000189159.96900.d9
发表时间：
2005-12-01
影响因子：
8.7
作者：
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通讯作者：
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