Frataxin deficiency increases cyclooxygenase 2 and prostaglandins in cell and animal models of Friedreich's ataxia.
Frataxin deficiency increases cyclooxygenase 2 and prostaglandins in cell and animal models of Friedreich's ataxia.
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DOI：
10.1093/hmg/ddu407
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发表时间：
2014-12-20
影响因子：
3.5
通讯作者：
Cortopassi G
中科院分区：
文献类型：
--
作者：
Hayashi G;Shen Y;Pedersen TL;Newman JW;Pook M;Cortopassi G
线粒体蛋白frataxin的遗传缺陷导致弗里德赖希共济失调（FRDA）；这种缺乏触发神经和心脏变性的机制尚不清楚。该疾病动物模型的神经组织微阵列显示抗氧化基因减少，炎症基因增加。环氧合酶（COX）衍生的氧脂类是重要的炎症介质。我们使用串联质谱法和elisa检测多种FRDA细胞和动物模型中的氧脂素水平。质谱分析显示敲除蛋白小鼠小脑样品中前列腺素、血栓素B2、15-HETE和11-HETE浓度升高。氧化脂素升高的一种可能的解释是，卵黄蛋白缺乏导致COX活性增加。在组成型COX1不变的情况下，诱导型COX2在两种弗里德赖希小鼠模型和弗里德赖希淋巴细胞中的表达升高超过1.35倍（P < 0.05）。与较高的COX2表达一致，其活性也比对照增加了58%。COX2的表达受多种转录因子驱动，包括激活蛋白1和cAMP反应元件结合蛋白，两者在小脑中均升高超过1.52倍。综上所述，这些结果支持了一种假设，即frataxin表达的减少导致了由响应活性氧增加的转录因子的增加而刺激的cox2介导的氧脂素合成的升高。这些发现支持FRDA的神经炎症机制，具有病理机制和治疗意义。
An inherited deficiency of the mitochondrial protein frataxin causes Friedreich's ataxia (FRDA); the mechanism by which this deficiency triggers neuro- and cardio-degeneration is unclear. Microarrays of neural tissue of animal models of the disease showed decreases in antioxidant genes, and increases in inflammatory genes. Cyclooxygenase (COX)-derived oxylipins are important mediators of inflammation. We measured oxylipin levels using tandem mass spectrometry and ELISAs in multiple cell and animal models of FRDA. Mass spectrometry revealed increases in concentrations of prostaglandins, thromboxane B2, 15-HETE and 11-HETE in cerebellar samples of knockin knockout mice. One possible explanation for the elevated oxylipins is that frataxin deficiency results in increased COX activity. While constitutive COX1 was unchanged, inducible COX2 expression was elevated over 1.35-fold (P < 0.05) in two Friedreich's mouse models and Friedreich's lymphocytes. Consistent with higher COX2 expression, its activity was also increased by 58% over controls. COX2 expression is driven by multiple transcription factors, including activator protein 1 and cAMP response element-binding protein, both of which were elevated over 1.52-fold in cerebella. Taken together, the results support the hypothesis that reduced expression of frataxin leads to elevation of COX2-mediated oxylipin synthesis stimulated by increases in transcription factors that respond to increased reactive oxygen species. These findings support a neuroinflammatory mechanism in FRDA, which has both pathomechanistic and therapeutic implications.
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影响因子：
3.7
作者：
Paupe, Vincent;Dassa, Emmanuel P.;Rustin, Pierre
通讯作者：
Rustin, Pierre
影响因子：
3.5
作者：
Michael, Susan;Petrocine, Simone V.;Koeppen, Arnulf H.
通讯作者：
Koeppen, Arnulf H.
DOI：
10.1073/pnas.94.14.7452
发表时间：
1997-07-08
影响因子：
11.1
作者：
Cossee, M;Schmitt, M;Koenig, M
通讯作者：
Koenig, M
影响因子：
158.5
作者：
Durr, A;Cossee, M;Koenig, M
通讯作者：
Koenig, M
影响因子：
8.8
作者：
Piro JR;Benjamin DI;Duerr JM;Pi Y;Gonzales C;Wood KM;Schwartz JW;Nomura DK;Samad TA
通讯作者：
Samad TA