Department of Endocrinology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China.
Department of Rheumatology, Mianyang Central Hospital, Mianyang, Sichuan 621000, P.R. China.
Mol Med Rep. 2022 Jan;25(1). doi: 10.3892/mmr.2021.12551. Epub 2021 Dec 1.
Uric acid (UA) is the final oxidation product of purine metabolism. Hyperuricemia has been previously reported to contribute to vascular endothelial dysfunction and the development of cardiovascular diseases, metabolic syndrome and chronic kidney diseases. In addition, it has been reported that fibroblast growth factor 21 (FGF21) can exert regulatory effects on UA‑induced lipid accumulation. Therefore, the present study aimed to investigate the possible role of FGF21 in HUVEC cell injury induced by UA. The study used UA to induce HUVEC cell injury, inhibited sirtuin 1 (Sirt1) expression using EX527 and overexpressed FGF21 by transfection. Subsequently, reverse transcription‑quantitative PCR was performed to measure the mRNA expression levels of FGF21, Sirt1 and inflammatory cytokines TNF‑α, IL‑1β and IL‑6, whereas western blotting was performed to measure their corresponding protein expression levels including FGF21, Sirt1, NLR family pyrin domain containing 3, pro‑caspase1, apoptosis‑associated speck‑like protein containing a CARD, activating transcription factor 4, C/EBP homologous protein and eukaryotic initiation factor 2. Furthermore, dichloro‑dihydro‑fluorescein diacetate staining was performed to measure intracellular reactive oxygen species (ROS) generation in HUVECs. The levels of ROS and nitric oxide were also quantified using commercial assay kits. The results demonstrated that overexpression of FGF21 significantly inhibited UA treatment‑induced endoplasmic reticulum (ER) stress, inflammation and oxidative stress in HUVECs. Furthermore, overexpression of FGF21 significantly activated Sirt1. The sirt1 inhibitor, EX527, significantly abrogated the suppressive effects of FGF21 overexpression on ER stress, inflammation and oxidative stress in UA‑stimulated HUVECs. To conclude, results of the present study suggested that FGF21 may attenuate UA‑induced ER stress, inflammation and vascular endothelial cell dysfunction by activating Sirt1. Therefore, FGF21 may be a potential effective target for the future treatment of vascular endothelial cell dysfunction.
尿酸（UA）是嘌呤代谢的最终氧化产物。高尿酸血症先前已被报道可导致血管内皮功能障碍以及心血管疾病、代谢综合征和慢性肾脏病的发生。此外，据报道，成纤维细胞生长因子 21（FGF21）可对 UA 诱导的脂质积累发挥调节作用。因此，本研究旨在探讨 FGF21 在 UA 诱导的人脐静脉内皮细胞（HUVEC）损伤中的可能作用。本研究使用 UA 诱导 HUVEC 细胞损伤，使用 EX527 抑制 Sirtuin 1（Sirt1）表达，并通过转染过表达 FGF21。随后，采用逆转录-定量 PCR 法检测 FGF21、Sirt1 及炎症细胞因子 TNF-α、IL-1β和 IL-6 的 mRNA 表达水平，采用蛋白质印迹法检测 FGF21、Sirt1、NLR 家族含pyrin 结构域蛋白 3、原半胱天冬酶 1、凋亡相关斑点样蛋白含有 CARD 结构域、激活转录因子 4、C/EBP 同源蛋白和真核起始因子 2 的相应蛋白表达水平。此外，采用二氯二氢荧光素二乙酸酯染色法检测 HUVEC 细胞内活性氧（ROS）的产生。还使用商业测定试剂盒定量测定 ROS 和一氧化氮的水平。结果表明，过表达 FGF21 可显著抑制 UA 处理诱导的 HUVEC 内质网（ER）应激、炎症和氧化应激。此外，过表达 FGF21 可显著激活 Sirt1。Sirt1 抑制剂 EX527 可显著消除 FGF21 过表达对 UA 刺激的 HUVEC 中 ER 应激、炎症和氧化应激的抑制作用。综上所述，本研究结果表明，FGF21 通过激活 Sirt1 可能减轻 UA 诱导的 ER 应激、炎症和血管内皮细胞功能障碍。因此，FGF21 可能成为未来治疗血管内皮细胞功能障碍的潜在有效靶点。
