RXR agonists inhibit high-glucose-induced oxidative stress by repressing PKC activity in human endothelial cells
RXR agonists inhibit high-glucose-induced oxidative stress by repressing PKC activity in human endothelial cells
复制标题
RXR 激动剂通过抑制人内皮细胞中的 PKC 活性来抑制高葡萄糖诱导的氧化应激
DOI：
10.1016/j.freeradbiomed.2007.12.022
复制
发表时间：
2008-04-01
影响因子：
7.4
通讯作者：
He, Ben
中科院分区：
文献类型：
--
作者：
Chai, Dajun;Wang, Binyao;He, Ben
已知维甲酸 X 受体 (RYR) 的激活可发挥抗动脉粥样硬化作用。然而，其根本机制仍不清楚。在这项研究中，我们研究了 RXR 激动剂 9-顺式视黄酸和 SR11237 对高葡萄糖诱导的人内皮细胞氧化应激的影响。我们的研究结果表明，高糖诱导的人脐静脉内皮细胞（HUVEC）氧化应激主要是通过激活烟酰胺腺嘌呤二核苷酸磷酸氧化酶的Nox4、gp91（phox）和p22（phox）成分介导的。用 RXR 激动剂处理内皮细胞可显着抑制高葡萄糖诱导的氧化应激以及 Nox4、gp91(phox) 和 P22(phox) 的表达。 RXR 激动剂的作用是由于它们抑制 Rac-1 激活。此外，RXR 激动剂可快速抑制高葡萄糖诱导的蛋白激酶 C (PKC)（Rac-1 的上游激活剂）的激活。为了研究 RXR 激动剂的快速抑制作用是否由 RXR 介导，我们检测了 RXR siRNA 下调 RXR 的效果。我们的结果表明，RXR siRNA 的表达很大程度上消除了 RXR 激动剂的作用，表明 RXR 表达的需要。有趣的是，广泛分布在 HUVEC 中的 RXR α 在高葡萄糖暴露后主要在细胞核中积累。用 RXR 激动剂处理细胞可以防止高葡萄糖的影响。因此，RXR 配体通过拮抗高糖诱导的 PKC 激活来快速抑制高糖诱导的氧化应激，而细胞质 RXR α 参与了这种调节。 (C) 2007 Elsevier Inc. 保留所有权利。
Activation of retinoid X receptor (RYR) is known to exert antiatherogenic effects. However, the underlying mechanism remains unclear. In this study.. we examined the effects of the RXR agonists 9-cis-retinoic acid and SR11237 on high-glucose-induced oxidative stress in human endothelial cells. Our results demonstrated that high-glucose-induced oxidative stress in human umbilical vein endothelial cells (HUVECs) was mainly mediated through its activation of the Nox4, gp91(phox), and p22(phox) components of nicotinamide adenine dinucleotide phosphate oxidase. Treatment of endothelial cells with RXR agonists resulted in significant inhibition of high-glucose-induced oxidative stress and expression of Nox4, gp91(phox), and P22(phox). The effect of RXR agonists was due to their inhibition of Rac-1 activation. Furthermore, RXR agonists rapidly inhibited high-glucose-induced activation of protein kinase C (PKC), an upstream activator of Rac-1. To study whether the rapid inhibitory effects of RXR agonists were mediated by RXR, we examined the effect of RXR downregulation by RXR siRNA. Our results showed that expression of RXR siRNA largely abrogated the effects of RXR agonists, suggesting the requirement of RXR expression. Interestingly, RXR alpha, which was diffusely distributed in HUVECs, accumulated mainly in the nucleus upon high glucose exposure. Treatment of cells with RXR agonists prevented the effect of high glucose. Thus, RXR ligands rapidly inhibit high-glucose-induced oxidative stress by antagonizing high-glucose-induced PKC activation, and cytoplasmic RXR alpha is implicated in this regulation. (C) 2007 Elsevier Inc. All rights reserved.