Redox activation of DUSP4 by N-acetylcysteine protects endothelial cells from Cd²⁺-induced apoptosis.
Redox activation of DUSP4 by N-acetylcysteine protects endothelial cells from Cd²⁺-induced apoptosis.
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DOI：
10.1016/j.freeradbiomed.2014.06.016
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发表时间：
2014-09
影响因子：
7.4
通讯作者：
Chen, Chun-An
中科院分区：
文献类型：
--
作者：
Barajas-Espinosa, Alma;Basye, Ariel;Jesse, Erin;Yan, Haixu;Quan, David;Chen, Chun-An
关键词：
氧化还原失衡是内皮功能障碍（艾德）的主要原因。在氧化应激下，许多调节内皮功能的关键蛋白质发生氧化修饰，导致ED。细胞中的主要还原源GSH的细胞水平可以通过可逆的蛋白质巯基修饰来显著调节细胞功能。N-乙酰半胱氨酸（NAC）是GSH生物合成的前体，对许多血管疾病有益;然而，这些益处的详细机制仍不清楚。从HPLC分析，NAC显着增加细胞GSH和BH 4水平。eNOS和DUSP 4（一种以半胱氨酸为活性残基的双特异性磷酸酶）的免疫印迹显示，这两种酶都被NAC上调。EPR自旋捕集进一步证明NAC增强了细胞的NO生成。长期暴露于Cd 2+有助于DUSP 4降解和p38和ERK 1/2的不受控制的激活，导致细胞凋亡。NAC处理可防止DUSP 4降解，并保护细胞免受Cd 2+诱导的凋亡。此外，增加的DUSP 4表达可以氧化还原调节p38和ERK 1/2通路的超活化，提供了抵抗Cd 2+毒性的存活机制。DUSP 4基因敲除进一步支持了DUSP 4是一种抗氧化基因的假设，该基因在eNOS翻译的调节中至关重要，从而保护免受Cd 2+诱导的胁迫。BSO对细胞内GSH的消耗使细胞对Cd 2+诱导的凋亡更敏感。用NAC预处理防止p38过度活化，从而保护内皮免受这种氧化应激。因此，NAC对DUSP 4激活的鉴定为未来的药物设计提供了新的靶点。
Redox imbalance is a primary cause for endothelial dysfunction (ED). Under oxidant stress, many critical proteins regulating endothelial function undergo oxidative modifications that lead to ED. Cellular levels of GSH, the primary reducing source in cells, can significantly regulate cell function via reversible protein thiol modification. N-Acetyl cysteine (NAC), a precursor for GSH biosynthesis, is beneficial for many vascular diseases; however, the detailed mechanism of these benefits is still not clear. From HPLC analysis, NAC significantly increases both cellular GSH and BH4 levels. Immunoblotting of eNOS and DUSP4, a dual-specificity phosphatase with a cysteine as its active residue, revealed that both enzymes are up-regulated by NAC. EPR spin-trapping further demonstrated that NAC enhances NO generation from cells. Long-term exposure to Cd2+ contributes to DUSP4 degradation and the uncontrolled activation of p38 and ERK1/2, leading to apoptosis. Treatment with NAC prevents DUSP4 degradation and protects cells against Cd2+-induced apoptosis. Moreover, the increased DUSP4 expression can redox regulate p38 and ERK1/2 pathways from hyper-activation, providing a survival mechanism against the toxicity of Cd2+. DUSP4 gene knockdown further supports the hypothesis that DUSP4 is an antioxidant gene, critical in the modulation of eNOS translation, and thus protects against Cd2+-induced stress. Depletion of intracellular GSH by BSO makes cells more susceptible to Cd2+-induced apoptosis. Pre-treatment with NAC prevents p38 over-activation and thus protects the endothelium from this oxidative stress. Therefore, the identification of DUSP4 activation by NAC provides a novel target for future drug design.
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影响因子：
64.8
作者：
Chen, Chun-An;Wang, Tse-Yao;Varadharaj, Saradhadevi;Reyes, Levy A.;Hemann, Craig;Talukder, M. A. Hassan;Chen, Yeong-Renn;Druhan, Lawrence J.;Zweier, Jay L.
通讯作者：
Zweier, Jay L.
影响因子：
4.8
作者：
Chrestensen, CA;Starke, DW;Mieyal, JJ
通讯作者：
Mieyal, JJ
影响因子：
5.8
作者：
Biswas, S;Chida, AS;Rahman, I
通讯作者：
Rahman, I
影响因子：
4.8
作者：
Lawan, Ahmed;Al-Harthi, Sameer;Plevin, Robin
通讯作者：
Plevin, Robin
影响因子：
20.1
作者：
Auger-Messier M;Accornero F;Goonasekera SA;Bueno OF;Lorenz JN;van Berlo JH;Willette RN;Molkentin JD
通讯作者：
Molkentin JD