Ding Yinjuan, Peng Yongmiao, Wu Huilan, Huang Yuqing, Sheng Ke, Li Chao, Chu Maoping, Ji Weiping, Guo Xiaoling
Basic Medical Research Center, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Basic Medical Research Center, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Structural Malformations in Children of Zhejiang Province, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; Key Laboratory of Children Genitourinary Diseases of Wenzhou, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Int Immunopharmacol. 2023 Apr;117:110028. doi: 10.1016/j.intimp.2023.110028. Epub 2023 Mar 17.
Kawasaki disease (KD) is an acute febrile rash illness among children of unknown etiology, with coronary artery injury. The main purpose of this study was to investigate the protective effects of liraglutide on KD, and elucidate the underlying mechanisms. The candida albicans water-soluble fraction (CAWS)-induced coronary arteritis of mouse KD model in vivo and tumor necrosis factor α (TNF-α) induced endothelial cell injury of human umbilical vein endothelial cell (HUVEC) model in vitro were used to explore the anti-inflammation and anti-apoptosis effects of liraglutide on KD. In vivo results showed that liraglutide could significantly alleviate the coronary artery injury of KD mice, as evidenced by the reduction of inflammatory infiltration around the coronary arteries, downregulation of inflammatory cytokines and chemokines expressions, and decrease of TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labeling) positive cell rates. The results in vitro also displayed that liraglutide could markedly relieve the inflammatory of TNF-α induced HUVECs through downregulating the expressions of inflammatory and chemokine indicators as well as inhibit TNF-α induced HUVEC apoptosis by the less ratio of apoptotic cells, the more loss of mitochondrial membrane potential (△Ψm), the lower level of intracellular reactive oxygen species (ROS), and the more ratio of BCL-2/BAX. Further in vivo and in vitro studies demonstrated that liraglutide could rescue endothelial cell injury through AMPK/mTOR/NF-κB pathway. In conclusion, liraglutide could play protective roles on KD through inhibiting endothelial cell inflammation and apoptosis via the activation of AMPK/mTOR/NF-κB pathway.
川崎病（KD）是一种病因不明的儿童急性发热出疹性疾病，可导致冠状动脉损伤。本研究的主要目的是探讨利拉鲁肽对KD的保护作用，并阐明其潜在机制。采用白色念珠菌水溶性成分（CAWS）诱导的小鼠KD模型体内冠状动脉炎和肿瘤坏死因子α（TNF-α）诱导的人脐静脉内皮细胞（HUVEC）模型体外内皮细胞损伤，探讨利拉鲁肽对KD的抗炎和抗凋亡作用。体内结果显示，利拉鲁肽可显著减轻KD小鼠的冠状动脉损伤，表现为冠状动脉周围炎症浸润减少、炎症细胞因子和趋化因子表达下调以及TUNEL（末端脱氧核苷酸转移酶dUTP缺口末端标记）阳性细胞率降低。体外结果还显示，利拉鲁肽可通过下调炎症和趋化因子指标的表达显著减轻TNF-α诱导的HUVEC炎症，并通过降低凋亡细胞比例、增加线粒体膜电位（△Ψm）损失、降低细胞内活性氧（ROS）水平以及增加BCL-2/BAX比例来抑制TNF-α诱导的HUVEC凋亡。进一步的体内和体外研究表明，利拉鲁肽可通过AMPK/mTOR/NF-κB途径挽救内皮细胞损伤。总之，利拉鲁肽可通过激活AMPK/mTOR/NF-κB途径抑制内皮细胞炎症和凋亡，从而对KD发挥保护作用。
