The novel anthraquinone compound Kanglexin prevents endothelial-to-mesenchymal transition in atherosclerosis by activating FGFR1 and suppressing integrinβ1/TGFβsignaling  

作　　者：Yixiu Zhao Zhiqi Wang Jing Ren Huan Chen Jia Zhu Yue Zhang Jiangfei Zheng Shifeng Cao Yanxi Li Xue Liu Na An Tao Ban Baofeng Yang Yan Zhang 

机构地区：[1]Department of Pharmacology(State-Province Key Laboratories of Biomedicine-Pharmaceutics of China,Key Laboratory of Cardiovascular Medicine Research,Ministry of Education),College of Pharmacy,Harbin Medical University,Harbin,150081,China [2]National Key Laboratory of Frigid Zone Cardiovascular Diseases(NKLFZCD),Harbin Medical University,Harbin,150081,China [3]College of Basic Medicine,Harbin Medical University,Harbin,150081,China [4]Heilongjiang Medical Academy,Harbin Medical University,Harbin,150081,China [5]Research Unit of Noninfectious Chronic Diseases in Frigid Zone,Chinese Academy of Medical Sciences,2019RU070,Harbin,150081,China

出　　处：《Frontiers of Medicine》2024年第6期1068-1086,共19页医学前沿(英文版)

基　　金：supported by the Basic Research Support Program for Outstanding Young Teachers of Heilongjiang Province(No.YQJH2023038);the National Natural Science foundation of China(Nos.82170431,82070312,82373868,82330011,and U21A20339);the Scientific Research Project of Provincial Scientific Research Institute of Heilongjiang Province(No.CZKYF2022-1-B007).

摘　　要：Endothelial-mesenchymal transition(EndMT)disrupts vascular endothelial integrity and induces atherosclerosis.Active integrinβ1 plays a pivotal role in promoting EndMT by facilitating TGFβ/Smad signaling in endothelial cells.Here,we report a novel anthraquinone compound,Kanglexin(KLX),which prevented EndMT and atherosclerosis by activating MAP4K4 and suppressing integrinβ1/TGFβsignaling.First,KLX effectively counteracted the EndMT phenotype and mitigated the dysregulation of endothelial and mesenchymal markers induced by TGFβ1.Second,KLX suppressed TGFβ/Smad signaling by inactivating integrinβ1 and inhibiting the polymerization of TGFβR1/2.The underlying mechanism involved the activation of FGFR1 by KLX,resulting in the phosphorylation of MAP4K4 and Moesin,which led to integrinβ1 inactivation by displacing Talin from itsβ-tail.Oral administration of KLX effectively stimulated endothelial FGFR1 and inhibited integrinβ1,thereby preventing vascular EndMT and attenuating plaque formation and progression in the aorta of atherosclerotic Apoe^(-/-)mice.Notably,KLX(20 mg/kg)exhibited superior efficacy compared with atorvastatin,a clinically approved lipid-regulating drug.In conclusion,KLX exhibited potential in ameliorating EndMT and retarding the formation and progression of atherosclerosis through direct activation of FGFR1.Therefore,KLX is a promising candidate for the treatment of atherosclerosis to mitigate vascular endothelial injury.

关 键 词：ATHEROSCLEROSIS EndMT INTEGRINΒ1 FGFR1 MAP4K4 Kanglexin 

分 类 号：R541.4[医药卫生—心血管疾病]