CD137 Signaling Promotes Endothelial Apoptosis by Inhibiting Nrf2 Pathway, and Upregulating NF-κB Pathway
CD137 Signaling Promotes Endothelial Apoptosis by Inhibiting Nrf2 Pathway, and Upregulating NF-κB Pathway
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CD137 信号传导通过抑制 Nrf2 通路和上调 NF-κB 通路促进内皮细胞凋亡
DOI：
10.1155/2020/4321912
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发表时间：
2020-06
影响因子：
4.6
通讯作者：
Jinchuan Yan
中科院分区：
文献类型：
--
作者：
Tianxin Geng;Yang Yan;Yue Zhang;Liangjie Xu;Guangyao Zang;Jinchuan Yan
研究背景氧化应激引起的内皮功能障碍和细胞凋亡可导致动脉粥样硬化的发展。我们的研究小组先前已经表明，CD 137信号有助于动脉粥样硬化的进展和斑块的脆弱性。本研究旨在探讨动脉粥样硬化中CD 137信号通路对内皮细胞凋亡的影响及其机制。方法收集11例急性心肌梗死患者和4例正常对照者的血清标本。在ApoE−/−小鼠中腹膜注射激动剂-CD 137重组蛋白用于确定CD 137信号传导是否可以在体内促进凋亡，并且用激动剂-CD 137重组蛋白处理人脐静脉内皮细胞，M5580（Nrf 2通路激动剂）和CAPE（NF-κB通路抑制剂），探讨NF-κB通路在CD 137信号诱导的内皮细胞凋亡中的作用。结果AMI患者血清Bcl-2水平低于对照组，TNF-α和sCD 137水平高于对照组。共聚焦显微镜和Western blot分析显示，与对照组相比，CD 137激动剂组Nrf 2的核转位明显受到抑制，其下游抗氧化酶的表达也明显降低。免疫荧光和Western blot结果显示激动剂-CD 137组NF-κB核转位增强，ELISA结果显示激动剂-CD 137组促炎细胞因子分泌增加。免疫荧光结果显示，CD 137激动剂组的ROS生成量高于对照组、M5580（Nrf 2通路激动剂）组和CAPE（NF-κB通路抑制剂）组。使用HUVECs的体外研究和使用高脂喂养的ApoE−/−小鼠的体内研究表明，CD 137激动剂组中凋亡内皮细胞的数量最多。相比之下，M5580和CAPE处理都能够减少CD 137诱导的EC凋亡。结论CD 137信号通路通过Nrf 2和NF-κB通路促进内皮细胞凋亡。
Background Endothelial dysfunction and apoptosis resulting from oxidative stress can lead to the development of atherosclerosis. Our group has previously showed that CD137 signaling contributes to the progression of atherosclerosis and the vulnerability of plaques. The aim of this study is to investigate the effects of CD137 signaling in atherosclerosis on endothelial cells (ECs) apoptosis and to explore the underlying mechanisms. Methods Serum samples were collected from 11 patients with acute myocardial infarction and 4 controls. Peritoneal injection of agonist-CD137 recombinant protein in ApoE−/− mice was used to determine whether CD137 signaling can promote apoptosis in vivo, and human umbilical vein endothelial cells treated with agonist-CD137 recombinant protein, M5580 (a Nrf2 pathway agonist) and CAPE (a NF-κB pathway inhibitor) were used to explore the effect of Nrf2 and NF-κB pathway in CD137 signaling-induced ECs apoptosis in vitro. Results ELISA showed that Bcl-2 in the serum of AMI patients was lower than that of the control group, while TNF-α and sCD137 were higher than that of the control group. Confocal microscopy and Western blot analysis showed that the nuclear translocation of Nrf2 in the agonist-CD137 group was significantly inhibited, and the expression of its downstream antioxidant enzymes was also decreased when compared with control. Immunofluorescence and Western blot results showed that the nuclear translocation of NF-κB in the agonist-CD137 group was enhanced, and ELISA results showed that the secretion of proinflammatory cytokines in the agonist-CD137 group was increased. Immunofluorescence results revealed that ROS production in the agonist-CD137 group was higher than that in control, M5580 (a Nrf2 pathway agonist) and CAPE (a NF-κB pathway inhibitor) groups. In vitro studies using HUVECs and in vivo studies using high-fat-fed ApoE−/− mice showed that the number of apoptotic endothelial cells was the highest in the agonist-CD137 group. By contrast, both M5580 and CAPE treatments were able to reduce CD137 induced ECs apoptosis. Conclusions Our results showed that CD137 signaling promotes ECs apoptosis through prooxidative and proinflammatory mechanisms, mediated by Nrf2 and NF-κB pathways, respectively.
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影响因子：
5.2
作者：
Jun Tang;D. Ramis-Cabrer;Xuejie Wang;E. Barreiro
通讯作者：
Jun Tang;D. Ramis-Cabrer;Xuejie Wang;E. Barreiro
影响因子：
5.8
作者：
Schulze, P Christian;Lee, Richard T
通讯作者：
Lee, Richard T
DOI：
10.1083/jcb.134.1.13
发表时间：
1996-07
期刊：
The Journal of cell biology
影响因子：
--
作者：
Grimm S;Bauer MK;Baeuerle PA;Schulze-Osthoff K
通讯作者：
Schulze-Osthoff K
OX40-OX40L 相互作用通过 NFATc1 在 ApoE 缺陷小鼠中促进淋巴细胞增殖和活化
影响因子：
3.7
作者：
Yan J;Su H;Xu L;Wang C
通讯作者：
Wang C
CD137信号传导的激活加速体内和体外血管钙化
影响因子：
3.5
作者：
Chen, Yao;Bangash, Abdul Basit;Yan, Jinchuan
通讯作者：
Yan, Jinchuan