Department and Institute of Pharmacology, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
Departments of Internal Medicine, College of Medicine, School of Medicine, Taipei Medical University, Taipei, Taiwan.
Cell Cycle. 2023 Nov;22(21-22):2409-2423. doi: 10.1080/15384101.2023.2296184. Epub 2024 Jan 18.
Chronic kidney disease (CKD) patients have a high risk of cardiovascular disease. Indoxyl sulfate (IS) is a uremic toxin that has been shown to inhibit nitric oxide production and cause cell senescence by inducing oxidative stress. High-density lipoprotein (HDL) has a protective effect on the cardiovascular system; however, its impacts on IS-damaged endothelial cells are still unknown. This study aimed to explore the effects of exogenous supplement of HDL on vascular endothelial cells in a uremia-mimic environment. Tube formation, migration, adhesion, and senescence assays were used to evaluate the cell function of human aortic endothelial cells (HAECs). Reactive oxygen species generation was measured by using Amplex red assay. L-NAME and MCI186 were used as a nitric oxide synthase inhibitor and a free radical scavenger, respectively. HDL exerted anti-inflammatory and antioxidant effects via HIF-1α/HO-1 activation and IL-1β/TNF-α/IL-6 inhibition in IS-stimulated HAECs. HDL improved angiogenesis ability through upregulating Akt/eNOS/VEGF/SDF-1 in IS-stimulated HAECs. HDL decreased endothelial adhesiveness via downregulating VCAM-1 and ICAM-1 in IS-stimulated HAECs. Furthermore, HDL reduced cellular senescence via upregulating SIRT1 and downregulating p53 in IS-stimulated HAECs. Importantly, the above beneficial effects of HDL were mainly due to its antioxidant ability. In conclusion, HDL exerted a comprehensive protective effect on vascular endothelial cells against damage from IS through its antioxidant ability. The results of this study might provide a theoretical basis for potential HDL supplementation in CKD patients with endothelial damage.
慢性肾脏病（CKD）患者心血管疾病风险较高。硫酸吲哚酚（IS）是一种尿毒症毒素，已被证明通过诱导氧化应激抑制一氧化氮产生并导致细胞衰老。高密度脂蛋白（HDL）对心血管系统具有保护作用；然而，其对 IS 损伤的内皮细胞的影响尚不清楚。本研究旨在探讨外源性补充 HDL 对尿毒症模拟环境中血管内皮细胞的影响。管形成、迁移、黏附和衰老测定用于评估人主动脉内皮细胞（HAECs）的细胞功能。使用 Amplex red 测定法测量活性氧的产生。L-NAME 和 MCI186 分别用作一氧化氮合酶抑制剂和自由基清除剂。HDL 通过 HIF-1α/HO-1 激活和 IL-1β/TNF-α/IL-6 抑制发挥抗炎和抗氧化作用在 IS 刺激的 HAECs 中。HDL 通过上调 Akt/eNOS/VEGF/SDF-1 改善 IS 刺激的 HAECs 中的血管生成能力。HDL 通过下调 IS 刺激的 HAECs 中的 VCAM-1 和 ICAM-1 降低内皮细胞黏附性。此外，HDL 通过上调 SIRT1 和下调 p53 降低 IS 刺激的 HAECs 中的细胞衰老。重要的是，HDL 的上述有益作用主要归因于其抗氧化能力。总之，HDL 通过其抗氧化能力对 IS 损伤的血管内皮细胞发挥全面的保护作用。本研究的结果可能为 CKD 患者内皮损伤时潜在的 HDL 补充提供理论依据。
