Activation of NF-E2-related factor-2 reverses biochemical dysfunction of endothelial cells induced by hyperglycemia linked to vascular disease.
Activation of NF-E2-related factor-2 reverses biochemical dysfunction of endothelial cells induced by hyperglycemia linked to vascular disease.
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DOI：
10.2337/db06-1003
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发表时间：
2008-10
期刊：
影响因子：
7.7
通讯作者：
Thornalley PJ
中科院分区：
文献类型：
--
作者：
Xue M;Qian Q;Adaikalakoteswari A;Rabbani N;Babaei-Jadidi R;Thornalley PJ
目的——萝卜硫素是转录因子 NF-E2 相关因子 2 (nrf2) 的激活剂，可通过启动子抗氧化反应元件 (ARE) 调节基因表达。 Nrf2 调节一系列保护酶和代谢酶的转录。本研究的目的是评估人微血管内皮细胞中萝卜硫素激活 nrf2 是否可以预防高血糖时的代谢功能障碍。研究设计和方法——将人微血管 HMEC-1 内皮细胞在低葡萄糖浓度和高葡萄糖浓度（分别为 5 mmol/l 和 30 mmol/l）下孵育，并通过核转位评估 nrf2 的激活。评估了萝卜硫素对生化功能障碍、活性氧 (ROS) 形成增加、己糖胺途径、蛋白激酶 C (PKC) 途径和甲基乙二醛形成增加等多种途径的影响。结果——萝卜硫素对nrf2的激活诱导了nrf2的核转位并增加了ARE相关基因的表达，例如转酮酶和谷胱甘肽还原酶的表达增加了三到五倍。高血糖会增加 ROS 的形成，这种效应与线粒体功能障碍有关，可被萝卜硫素阻止。通过敲除 nrf2 和转酮醇酶表达，ROS 形成进一步增加。这也消除了萝卜硫素的抵消作用，表明 nrf2 的介导以及转酮醇酶表达的相关增加。萝卜硫素还可以防止高血糖诱导的己糖胺和 PKC 途径的激活，并防止糖化剂甲基乙二醛的细胞积累和排泄增加。结论——我们得出的结论是，nrf2的激活可以预防高血糖引起的内皮细胞的生化功能障碍和相关功能反应，其中转酮醇酶表达的增加起着关键作用。
OBJECTIVE—Sulforaphane is an activator of transcription factor NF-E2–related factor-2 (nrf2) that regulates gene expression through the promoter antioxidant response element (ARE). Nrf2 regulates the transcription of a battery of protective and metabolic enzymes. The aim of this study was to assess whether activation of nrf2 by sulforaphane in human microvascular endothelial cells prevents metabolic dysfunction in hyperglycemia. RESEARCH DESIGN AND METHODS—Human microvascular HMEC-1 endothelial cells were incubated in low and high glucose concentrations (5 and 30 mmol/l, respectively), and activation of nrf2 was assessed by nuclear translocation. The effects of sulforaphane on multiple pathways of biochemical dysfunction, increased reactive oxygen species (ROS) formation, hexosamine pathway, protein kinase C (PKC) pathway, and increased formation of methylglyoxal were assessed. RESULTS—Activation of nrf2 by sulforaphane induced nuclear translocation of nrf2 and increased ARE-linked gene expression, for example, three- to fivefold increased expression of transketolase and glutathione reductase. Hyperglycemia increased the formation of ROS—an effect linked to mitochondrial dysfunction and prevented by sulforaphane. ROS formation was increased further by knockdown of nrf2 and transketolase expression. This also abolished the counteracting effect of sulforaphane, suggesting mediation by nrf2 and related increase of transketolase expression. Sulforaphane also prevented hyperglycemia-induced activation of the hexosamine and PKC pathways and prevented increased cellular accumulation and excretion of the glycating agent methylglyoxal. CONCLUSIONS—We conclude that activation of nrf2 may prevent biochemical dysfunction and related functional responses of endothelial cells induced by hyperglycemia in which increased expression of transketolase has a pivotal role.