Astragaloside IV Inhibits Bleomycin-Induced Ferroptosis in Human Umbilical Vein Endothelial Cells by Mediating LPC.
Astragaloside IV Inhibits Bleomycin-Induced Ferroptosis in Human Umbilical Vein Endothelial Cells by Mediating LPC.
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黄芪甲苷 IV 通过介导 LPC 抑制人脐静脉内皮细胞中博来霉素诱导的铁死亡
DOI：
10.1155/2021/6241242
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发表时间：
2021
影响因子：
--
通讯作者：
Zhang L
中科院分区：
文献类型：
--
作者：
Sheng S;Xu J;Liang Q;Hong L;Zhang L
铁凋亡作为一种铁依赖的程序性细胞死亡途径，可导致多种心血管疾病。黄芪甲苷（AS-IV）是从黄芪中分离纯化的一种有效成分，具有保护内皮功能和促进血管再生的作用。然而，AS-IV在铁凋亡中所起的作用仍然未知。在这项研究中，使用LC/MS探索了用/不用博莱霉素和/或AS-IV处理的HUVEC中的脂质代谢组学。通过GO和途径富集分析进一步鉴定了组间最具差异的代谢物。采用CCK-8法检测溶血磷脂酰胆碱（LPC）、AS-IV和FIN 56对细胞活力的影响，β-半乳糖苷酶染色法检测其对细胞衰老的影响，流式细胞术检测脂质ROS水平，透射电镜和细胞铁水平检测其对铁凋亡的影响。通过实时荧光定量PCR和Western blot分析研究了其相关机制。结果表明，LPC作为最具差异性的代谢产物，随着其浓度的增加，抑制细胞活力，但促进细胞凋亡和衰老。此外，降低的细胞活性，增加铁离子和脂质ROS水平，并增强LPC处理诱导的细胞衰老都显着逆转AS-IV，但进一步增强FIN 56处理。由LPC处理引起的线粒体形态的变化被AS-IV处理显著减轻，而用FIN 56处理逆转了这些现象。此外，AS-IV部分上调LPC降低的SLC 7A 11和GPX 4表达水平。然而，FIN 56治疗阻止了这些变化。综上所述，我们的数据表明，AS-IV可以作为一种新的药物，用于治疗铁中毒相关疾病。
Ferroptosis, as an iron-dependent programmed cell death pathway, can induce a variety of cardiovascular diseases. Astragaloside IV (AS-IV), which is purified from Astragalus membranaceus, can protect endothelial function and promote vascular regeneration. However, the role played by AS-IV in ferroptosis remains unknown. In this study, the lipid metabolomics in HUVECs treated with/without bleomycin and/or AS-IV were explored using LC/MS. The most differential metabolite between groups was further identified via GO and pathway enrichment analyses. The effects of lysophosphatidylcholine (LPC), AS-IV, and FIN56 on cell viability were explored using the CCK-8 assay, their effects on cell senescence were examined by β-galactosidase staining, and their effects on ferroptosis were detected by a flow cytometric analysis of lipid ROS levels, transmission electron microscopy, and an assay for cellular iron levels. The related mechanisms were investigated by real-time PCR and Western blot assays. Our results showed that LPC, as the most differential metabolite, inhibited cell viability but promoted cell apoptosis and senescence as its concentration increased. Also, the decreased cell activity, increased iron ion and lipid ROS levels, and the enhanced cell senescence induced by LPC treatment were all significantly reversed by AS-IV but further enhanced by FIN56 treatment. The changes in mitochondrial morphology caused by the LPC treatment were significantly alleviated by the AS-IV treatment, while treatment with FIN56 reversed those phenomena. Moreover, AS-IV partially upregulated the levels of SLC7A11 and GPX4 expression which were reduced by LPC. However, those changes were prevented by FIN56 treatment. In conclusion, our data suggested that AS-IV could serve as a novel drug for treating ferroptosis-related diseases.
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