Abstract
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.
Highlights
Vascular endothelial cells, as important components of arterial intima, do form the barrier between blood and tissues and regulate blood vessel function and maintain a stable internal environment [1, 2]
To explore the effects of bleomycin (MedChem Express, NJ, USA) and Astragaloside IV (AS-IV, Solarbio, Beijing, China) on lipid metabonomics in Human umbilical vein endothelial cells (HUVECs), the cells were treated with bleomycin (50 μM) to induce cell senescence; after which, they were coincubated with AS-IV (50 μM) and bleomycin to explore the effect of AS-IV
To determine whether the metabolites in HUVECs had changed during bleomycininduced cell senescence and explore the effect of AS-IV on cell senescence, the HUVECs in each group were collected and used for nontargeted metabolomic studies conducted by LC/MS
Summary
As important components of arterial intima, do form the barrier between blood and tissues and regulate blood vessel function and maintain a stable internal environment [1, 2]. When endothelial cells are continuously damaged, vascular pathological changes are often induced that make them susceptible to further damage caused by peroxidation. This additional damage leads to thickening of the vessel wall and lumen narrowing [3], which promotes thrombosis and vascular necrosis [2, 4]. Vascular cell senescence often induces vascular aging, which can lead to a variety of cardiovascular disorders such as atherosclerotic plaque formation, myocardial infarction, and heart failure [5, 6]. It is still important to develop new drugs for treating and preventing cardiovascular metabolic diseases
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