Role of ferroptosis in the process of diabetes-induced endothelial dysfunction.
Role of ferroptosis in the process of diabetes-induced endothelial dysfunction.
复制标题
铁死亡在糖尿病引起的内皮功能障碍过程中的作用。
DOI：
10.4239/wjd.v12.i2.124
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发表时间：
2021-02-15
影响因子：
4.2
通讯作者：
Wang D
中科院分区：
文献类型：
--
作者：
Luo EF;Li HX;Qin YH;Qiao Y;Yan GL;Yao YY;Li LQ;Hou JT;Tang CC;Wang D
内皮功能障碍是糖尿病的一个标志，是糖尿病心血管并发症发病机制的关键和始发因素。然而，其基本机制仍未完全了解。铁死亡是一种新定义的由细胞代谢和铁依赖性脂质过氧化驱动的调节性细胞死亡。尽管铁死亡参与疾病发病机制已在癌症和退行性疾病中得到证实，但铁死亡在糖尿病内皮功能障碍的发病机制中的参与仍不清楚。研究铁死亡在糖尿病引起的内皮功能障碍中的作用及其潜在机制。用高糖（HG）、白细胞介素-1β（IL-1β）和铁死亡抑制剂处理人脐静脉内皮细胞（HUVEC），然后检测细胞活力、活性氧（ROS）和铁死亡相关标记蛋白。为了进一步确定p53-xCT（Xc-）-谷胱甘肽（GSH）系统的底物特异性亚基是否参与HG和IL-1β诱导的铁死亡，用p53小干扰核糖核酸或NC小干扰核糖核酸瞬时转染HUVEC，然后用HG和IL-1β处理。然后评估细胞活力、ROS 和铁死亡相关标记蛋白。此外，我们还检测了db/db小鼠主动脉中xCT和p53的表达。研究发现，HG 和 IL-1β 会诱导 HUVEC 中的铁死亡，铁死亡抑制剂去铁胺和铁他汀-1 的保护作用证明了这一点，导致脂质 ROS 增加和细胞活力下降。从机制上讲，HG 和 IL-1β 诱导的 p53-xCT-GSH 轴激活可增强 HUVEC 中的铁死亡。此外，在 db/db 小鼠的主动脉内皮中观察到 xCT 降低和去内皮化区域的存在。铁死亡参与内皮功能障碍，p53-xCT-GSH 轴激活在内皮细胞铁死亡和内皮功能障碍中起着至关重要的作用。
Endothelial dysfunction, a hallmark of diabetes, is a critical and initiating contributor to the pathogenesis of diabetic cardiovascular complications. However, the underlying mechanisms are still not fully understood. Ferroptosis is a newly defined regulated cell death driven by cellular metabolism and iron-dependent lipid peroxidation. Although the involvement of ferroptosis in disease pathogenesis has been shown in cancers and degenerative diseases, the participation of ferroptosis in the pathogenesis of diabetic endothelial dysfunction remains unclear. To examine the role of ferroptosis in diabetes-induced endothelial dysfunction and the underlying mechanisms. Human umbilical vein endothelial cells (HUVECs) were treated with high glucose (HG), interleukin-1β (IL-1β), and ferroptosis inhibitor, and then the cell viability, reactive oxygen species (ROS), and ferroptosis-related marker protein were tested. To further determine whether the p53-xCT (the substrate-specific subunit of system Xc-)-glutathione (GSH) axis is involved in HG and IL-1β induced ferroptosis, HUVECs were transiently transfected with p53 small interfering ribonucleic acid or NC small interfering ribonucleic acid and then treated with HG and IL-1β. Cell viability, ROS, and ferroptosis-related marker protein were then assessed. In addition, we detected the xCT and p53 expression in the aorta of db/db mice. It was found that HG and IL-1β induced ferroptosis in HUVECs, as evidenced by the protective effect of the ferroptosis inhibitors, Deferoxamine and ferrostatin-1, resulting in increased lipid ROS and decreased cell viability. Mechanistically, activation of the p53-xCT-GSH axis induced by HG and IL-1β enhanced ferroptosis in HUVECs. In addition, a decrease in xCT and the presence of de-endothelialized areas were observed in the aortic endothelium of db/db mice. Ferroptosis is involved in endothelial dysfunction and p53-xCT-GSH axis activation plays a crucial role in endothelial cell ferroptosis and endothelial dysfunction.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
铁毒性及其在各种脑部疾病中的作用。
影响因子：
5.1
作者：
Weiland A;Wang Y;Wu W;Lan X;Han X;Li Q;Wang J
通讯作者：
Wang J
影响因子：
37.8
作者：
Verma, S;Anderson, TJ
通讯作者：
Anderson, TJ
影响因子：
5
作者：
Yokoyama, Masataka;Shimizu, Ippei;Minamino, Tohru
通讯作者：
Minamino, Tohru
影响因子：
64.8
作者：
Jiang, Le;Kon, Ning;Li, Tongyuan;Wang, Shang-Jui;Su, Tao;Hibshoosh, Hanina;Baer, Richard;Gu, Wei
通讯作者：
Gu, Wei