Carbon monoxide protects against oxidant-induced apoptosis via inhibition of Kv2.1
Carbon monoxide protects against oxidant-induced apoptosis via inhibition of Kv2.1
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DOI：
10.1096/fj.10-173450
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发表时间：
2011-05-01
期刊：
影响因子：
4.8
通讯作者：
Peers, Chris
中科院分区：
文献类型：
--
作者：
Dallas, Mark L.;Boyle, John P.;Peers, Chris
氧化应激诱导神经元凋亡，并与脑缺血、头部创伤和年龄相关的神经退行性疾病有关。这一过程的早期步骤是通过K+通道丢失细胞内K+，有证据表明K(v)2.1在这方面特别重要，它在响应凋亡刺激时迅速插入质膜。神经元氧化应激的另一个特征是诱导酶血红素氧化酶-1 （HO-1）的上调，该酶分解血红素生成胆绿素、铁离子和一氧化碳（CO）。一氧化碳提供神经元保护，防止压力，如中风和兴奋性毒性，尽管潜在的机制尚未阐明。在这里，我们证明了CO可逆抑制K(v)2.1。CO对通道的抑制涉及活性氧和蛋白激酶G活性。HEK293细胞中K(v)2.1的过度表达增加了它们对氧化诱导的细胞凋亡的易感性，而CO可以逆转这种易感性。在海马神经元中，CO选择性地抑制K(v)2.1，逆转氧化诱导的K+电流密度的急剧增加，并对氧化诱导的细胞凋亡提供显著的保护。我们的研究结果提供了一种新的机制来解释CO对氧化细胞凋亡的神经保护作用，这有可能在氧化应激情况下提供神经保护。-Dallas， M. L, Boyle， J. P, Milligan， C. J, Sayer， R., Kerrigan， T. L, McKinstry， C, Lu， P, Mankouri， J, Harris， M, Scragg， J. L, Pearson， H. A, Peers， C.一氧化碳通过抑制K(v)2.1来保护氧化诱导的细胞凋亡。中国生物医学工程学报，21(2):444 - 444（2011）。www.fasebj.org
Oxidative stress induces neuronal apoptosis and is implicated in cerebral ischemia, head trauma, and age-related neurodegenerative diseases. An early step in this process is the loss of intracellular K+ via K+ channels, and evidence indicates that K(v)2.1 is of particular importance in this regard, being rapidly inserted into the plasma membrane in response to apoptotic stimuli. An additional feature of neuronal oxidative stress is the up-regulation of the inducible enzyme heme oxygenase-1 (HO-1), which catabolizes heme to generate biliverdin, Fe2+, and carbon monoxide (CO). CO provides neuronal protection against stresses such as stroke and excitotoxicity, although the underlying mechanisms are not yet elucidated. Here, we demonstrate that CO reversibly inhibits K(v)2.1. Channel inhibition by CO involves reactive oxygen species and protein kinase G activity. Overexpression of K(v)2.1 in HEK293 cells increases their vulnerability to oxidant-induced apoptosis, and this is reversed by CO. In hippocampal neurons, CO selectively inhibits K(v)2.1, reverses the dramatic oxidant-induced increase in K+ current density, and provides marked protection against oxidant-induced apoptosis. Our results provide a novel mechanism to account for the neuroprotective effects of CO against oxidative apoptosis, which has potential for therapeutic exploitation to provide neuronal protection in situations of oxidative stress.-Dallas, M. L., Boyle, J. P., Milligan, C. J., Sayer, R., Kerrigan, T. L., McKinstry, C., Lu, P., Mankouri, J., Harris, M., Scragg, J. L., Pearson, H. A., Peers, C. Carbon monoxide protects against oxidant-induced apoptosis via inhibition of K(v)2.1. FASEB J. 25, 1519-1530 (2011). www.fasebj.org