School of Forensic Medicine, Xinxiang Medical University.
Xinxiang Key Laboratory of Metabolism and Integrative Physiology.
J Atheroscler Thromb. 2023 Feb 1;30(2):138-149. doi: 10.5551/jat.63460. Epub 2022 Mar 19.
Roles of fibroblast growth factor 23 (FGF23) in endothelial dysfunction remain controversial, and evidence from population-based studies is lacking. The present study aimed to explore the effects of FGF23 on endothelial dysfunction on the basis of both clinical data of patients with coronary artery disease (CAD) and the in vitro research in human umbilical vein endothelial cells (HUVECs).
A total of 321 CAD patients were enrolled after coronary angiography, brachial artery flow-mediated dilation (FMD) was assessed using ultrasound equipment. Serum FGF23, nitric oxide (NO), and endothelin-1 (ET-1) were detected via enzyme-linked immunosorbent assay. Apoptosis was determined using the annexin V-fluorescein isothiocyanate/propidium lodide apoptosis detection kit. Cell migration was evaluated by wound healing and transwell migration assays. Reactive oxide species levels were determined using fluorescent probes, and NF-κB p65 nuclear translocation was assessed via immunofluorescence.
Serum FGF23 was significantly increased in CAD patients combined with severe endothelial dysfunction (FMD ＜2%) compared to those with FMD ≥ 2% (P＜0.001). Furthermore, the levels of FGF23 were negatively correlated with NO, whereas positively correlated with ET-1 both in unadjusted analysis and multivariate-adjusted analysis. In HUVECs, FGF23 interfered with the bioavailability of NO via increased oxidative stress. Moreover, FGF23 directly impaired the endothelium by promoting HUVECs apoptosis and attenuating the migration of HUVECs. Additional experiments showed that FGF23 induced endothelial injury through activation of the NF-κB signaling pathway.
Elevated FGF23 is clinically associated with endothelial dysfunction in CAD patients, and FGF23 impairs endothelial function through activation of the NF-κB signaling pathway.
成纤维细胞生长因子 23（FGF23）在血管内皮功能障碍中的作用仍存在争议，且缺乏基于人群的研究证据。本研究旨在基于冠心病（CAD）患者的临床数据和人脐静脉内皮细胞（HUVEC）的体外研究，探讨 FGF23 对血管内皮功能障碍的影响。
对冠状动脉造影后的 321 例 CAD 患者进行了研究，使用超声设备评估肱动脉血流介导的扩张（FMD）。通过酶联免疫吸附试验检测血清 FGF23、一氧化氮（NO）和内皮素-1（ET-1）。使用膜联蛋白 V-异硫氰酸荧光素/碘化丙啶凋亡检测试剂盒检测细胞凋亡。通过划痕愈合和 Transwell 迁移实验评估细胞迁移。使用荧光探针测定活性氧（ROS）水平，并通过免疫荧光法评估 NF-κB p65 核转位。
与 FMD≥2%的 CAD 患者相比，伴有严重内皮功能障碍（FMD＜2%）的 CAD 患者血清 FGF23 显著升高（P＜0.001）。此外，未经校正分析和多元校正分析均显示，FGF23 水平与 NO 呈负相关，与 ET-1 呈正相关。在 HUVEC 中，FGF23 通过增加氧化应激干扰 NO 的生物利用度。此外，FGF23 通过促进 HUVEC 凋亡和抑制 HUVEC 迁移，直接损害内皮细胞。进一步的实验表明，FGF23 通过激活 NF-κB 信号通路诱导内皮损伤。
升高的 FGF23 与 CAD 患者的内皮功能障碍有关，FGF23 通过激活 NF-κB 信号通路损害内皮功能。
