Oscillating glucose and constant high glucose induce endoglin expression in endothelial cells: the role of oxidative stress
Oscillating glucose and constant high glucose induce endoglin expression in endothelial cells: the role of oxidative stress
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DOI：
10.1007/s00592-014-0670-3
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发表时间：
2015-06-01
影响因子：
3.8
通讯作者：
Ceriello, Antonio
中科院分区：
文献类型：
--
作者：
La Sala, Lucia;Pujadas, Gemma;Ceriello, Antonio
高糖诱导的氧化应激被认为是糖尿病血管内皮细胞损伤的介质之一。在病理情况下，主要的内皮蛋白endoglin在血管中过度表达，但对其与糖尿病血管并发症的关系知之甚少。为了阐明endoglin在内皮损伤中的作用，我们试图确定高糖和振荡糖对其表达的影响。此外，我们还评估了Kruppel样因子6(KLF-6)和低氧诱导因子-1α(HIF-1α)的激活作为endoglin表达的可能调节因素。为探讨氧化应激的可能作用，评价抗氧化剂α-硫辛酸(ALA)的作用以及NAD(P)H：奎宁氧化还原酶-1(NQO-1)和血红素加氧酶-1(HO-1)介导的细胞抗氧化反应。原代人脐静脉内皮细胞在正常、高糖和振荡葡萄糖(分别为5、25和5/25 mmol/L每24 h)中培养21天。在振荡和高糖状态下，其可溶性形式(Seng)、KLF-6和HIF-1α显著升高。同时，DNA氧化应激标志物8-OHdG和H_2A.X升高。此外，在葡萄糖暴露期间，ENG基因转录速率增加，同时伴随着KLF-6核转位的增加。ALA显著减少了所有这些现象。有趣的是，在振荡和慢性高糖过程中，NQO-1和HO-1没有增加，但ALA诱导了它们的过度表达。这些发现为Endoglin在高糖介导的HUVECs血管损伤调控中的作用以及氧化应激在其中的作用提供了新的线索。
High glucose-induced oxidative stress has been suggested as one of the mediators of endothelial damage in diabetes. The major endothelial protein, endoglin, has been found overexpressed in the vessels during pathological situations, but little is known about its relation to diabetic vascular complications. To clarify the role of endoglin in endothelial injury, we sought to determine the effects of high and oscillating glucose on its expression.Furthermore, the activation of the Kruppel-like factor 6 (KLF-6) and the hypoxia-inducible factor-1 alpha (HIF-1 alpha) as possible regulators of endoglin expression has been evaluated. The possible role of the oxidative stress has been studied evaluating the effects of the antioxidant alpha-lipoic acid (ALA) and the cellular antioxidant response mediated by NAD(P)H:quinine-oxido-reductase-1 (NQO-1) and heme oxygenase-1 (HO-1).Primary HUVECs were cultured for 21 days in normal, high and oscillating glucose (5, 25 and 5/25 mmol/l every 24 h, respectively) with/without ALA. In oscillating and high glucose total endoglin, its soluble form (sEng), KLF-6 and HIF-1 alpha were significantly increased. Simultaneously, the oxidative DNA stress markers 8-OHdG and H2A.X were elevated. Moreover, ENG gene transcriptional rate increased during glucose exposures concomitantly with increased KLF-6 nuclear translocations. ALA significantly reduced all these phenomena. Interestingly, during oscillating and chronic high glucose, NQO-1 and HO-1 did not increase, but ALA induced their overexpression.Together, these findings provide novel clue about endoglin in the regulation of high glucose-mediated vascular damage in HUVECs and the role of oxidative stress in this regulation.