Duan Yanru, Zhang Shihan, Xing Yuanyuan, Wu Ye, Zhao Wen, Xie Pinxue, Zhang Huina, Gao Xinxiao, Qin Yanwen, Wang Yajing, Ma Xinliang, Du Yunhui, Liu Huirong
Department of Physiology & Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, P. R. China.
Medical Oncology Department, Pediatric Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing Key Laboratory of Pediatric Hematology Ocology, Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing 100045, P. R. China.
iScience. 2023 Mar 20;26(4):106428. doi: 10.1016/j.isci.2023.106428. eCollection 2023 Apr 21.
While adiponectin (APN) was known to significantly abolish the diabetic endothelial inflammatory response, the specific mechanisms have yet to be elucidated. Aortic vascular tissues from mice fed normal and high-fat diets (HFD) were analyzed by transcriptome analysis. GO functional annotation showed that APN inhibited vascular endothelial inflammation in an APPL1-dependent manner. We confirmed that activation of the Wnt/β-catenin signaling plays a key role in APN-mediated anti-inflammation. Mechanistically, APN promoted APPL1/reptin complex formation and β-catenin nuclear translocation. Simultaneously, we identified APN promoted the expression of CD44 by activating TCF/LEF in an APPL1-mediated manner. Clinically, the serum levels of APN and CD44 were decreased in diabetes; the levels of these two proteins were positively correlated. Functionally, treatment with CD44 C-terminal polypeptides protected diabetes-induced vascular endothelial inflammation . Collectively, we provided a roadmap for APN-inhibited vascular inflammatory effects and CD44 might represent potential targets against the diabetic endothelial inflammatory effect.
虽然已知脂联素（APN）能显著消除糖尿病患者的内皮炎症反应，但其具体机制尚未阐明。通过转录组分析对喂食正常饮食和高脂饮食（HFD）的小鼠的主动脉血管组织进行了分析。基因本体（GO）功能注释表明，APN以依赖APPL1的方式抑制血管内皮炎症。我们证实，Wnt/β-连环蛋白信号通路的激活在APN介导的抗炎作用中起关键作用。从机制上讲，APN促进了APPL1/瑞ptin复合物的形成和β-连环蛋白的核转位。同时，我们发现APN以APPL1介导的方式通过激活TCF/LEF促进CD44的表达。临床上，糖尿病患者血清中APN和CD44水平降低；这两种蛋白的水平呈正相关。在功能上，用CD44 C末端多肽治疗可保护糖尿病诱导的血管内皮炎症。总的来说，我们为APN抑制血管炎症作用提供了一个路径图，并且CD44可能是对抗糖尿病内皮炎症作用的潜在靶点。
