Zhao Zunlan, Zhao Yingshuai, Zhang Yuqing, Shi Weili, Li Xiqing, Shyy John Y-J, He Ming, Wang Liuyi
Department of General Medicine, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
FASEB J. 2021 Jun;35(6):e21613. doi: 10.1096/fj.202100337R.
Gout is a multifaceted inflammatory disease involving vascular impairments induced by hyperuricemia. Experiments using human umbilical vein endothelial cells treated with uric acid (UA), monosodium urate (MSU), or serum from gout patients showed increased expression of pro-inflammatory genes (ie, VCAM1, ICAM1, CYR61, CCNA1, and E2F1) with attendant increase in monocyte adhesion. Mechanistically, UA- or MSU-induced SREBP2 expression and its transcriptional activity. RNA sequencing analysis and real-time PCR showed the induction of YAP signaling and pro-inflammatory pathways in HUVECs transfected with adenovirus-SREBP2. The SREBP2 knockdown by siRNA partially abolished UA- or MSU-induced YAP activity, pro-inflammatory gene expression, and monocytes adhesion. Vascular intima from transgenic mice overexpressing SREBP2 in endothelium or mice with hyperuricemia exhibited activated YAP signaling and increased expression of pro-inflammatory genes. Betulin, an SREBP pharmacological inhibitor, attenuated the UA-, MSU-, or gout serum-induced endothelial cell inflammation and dysfunction. In the human study, endothelial cell function, assessed by EndoPAT, was negatively correlated with serum UA level among gouty patients and healthy controls. Collectively, UA or MSU causes endothelial dysfunction via SREBP2 transactivation of YAP. Betulin inhibition of SREBP2 may restrain gout-induced endothelial dysfunction.
痛风是一种多方面的炎症性疾病，涉及高尿酸血症引起的血管损伤。使用尿酸（UA）、尿酸钠（MSU）或痛风患者血清处理人脐静脉内皮细胞的实验表明，促炎基因（即VCAM1、ICAM1、CYR61、CCNA1和E2F1）的表达增加，同时单核细胞粘附增加。从机制上讲，UA或MSU诱导SREBP2表达及其转录活性。RNA测序分析和实时PCR显示，在用腺病毒-SREBP2转染的人脐静脉内皮细胞中YAP信号通路和促炎途径被诱导。通过siRNA敲低SREBP2可部分消除UA或MSU诱导的YAP活性、促炎基因表达和单核细胞粘附。在内皮中过表达SREBP2的转基因小鼠或高尿酸血症小鼠的血管内膜表现出激活的YAP信号和促炎基因表达增加。桦木醇，一种SREBP药理学抑制剂，可减轻UA、MSU或痛风血清诱导的内皮细胞炎症和功能障碍。在人体研究中，通过EndoPAT评估的内皮细胞功能在痛风患者和健康对照中与血清UA水平呈负相关。总的来说，UA或MSU通过YAP的SREBP2反式激活导致内皮功能障碍。桦木醇对SREBP2的抑制作用可能会抑制痛风诱导的内皮功能障碍。
