Urolithin A promotes atherosclerotic plaque stability by limiting inflammation and hypercholesteremia in Apolipoprotein E–deficient mice  

作　　者：Meng-yun Xu Jing-jing Xu Li-jing Kang Zheng-hong Liu Mei-ming Su Wen-qi Zhao Zhi-hua Wang Lu Sun Jian-bo Xiao Paul C.Evans Xiao-yu Tian Li Wang Yu Huang Xin-miao Liang Jian-ping Weng Suo-wen Xu 

机构地区：[1]Department of Endocrinology,Institute of Endocrine and Metabolic Disease,The First Affiliated Hospital of USTC,Division of Life Sciences and Medicine,Clinical Research Hospital of Chinese Academy of Sciences(Hefei),University of Science and Technology of China,Hefei,230000,China [2]Department of Obstetrics and Gynecology,The First Affiliated Hospital of USTC,Division of Life Sciences and Medicine,University of Science and Technology of China,Hefei,230001,China [3]Department of Biomedical Sciences,City University of Hong Kong,Hong Kong,China [4]Universidade de Vigo,Department of Analytical and Food Chemistry,Faculty of Sciences,Ourense,32004,Spain [5]Centre for Biochemical Pharmacology,William Harvey Research Institute,Barts and The London Faculty of Medicine and Dentistry,Queen Mary University of London,London,EC1M 6BQ,UK [6]School of Biomedical Sciences,Heart and Vascular Institute,Faculty of Medicine,The Chinese University of Hong Kong,Shatin NT,Hong Kong SAR,999077,China [7]CAS Key Laboratory of Separation Science for Analytical Chemistry,Dalian Institute of Chemical Physics,Chinese Academy of Sciences,Dalian,116000,China

出　　处：《Acta Pharmacologica Sinica》2024年第11期2277-2289,共13页中国药理学报（英文版）

基　　金：supported by grants from the National Key R&D Program of China(Grant No.2021YFC2500500);the National Natural Science Foundation of China(Grant No.82370444,82070464,82003741);the Strategic Priority Research Program of the Chinese Academy of Sciences(Grant No.XDB38010100);supported by the Program for Innovative Research Team of The First Affiliated Hospital of USTC(CXGG02);Anhui Provincial Key Research and Development Program(Grant No.202104j07020051);Anhui Provincial Natural Science Foundation(Grant No.2208085J08).

摘　　要：Urolithin A(UroA),a dietary phytochemical,is produced by gut bacteria from fruits rich in natural polyphenols ellagitannins(ETs).The efficiency of ETs metabolism to UroA in humans depends on gut microbiota.UroA has shown a variety of pharmacological activities.In this study we investigated the effects of UroA on atherosclerotic lesion development and stability.Apolipoprotein E-deficient(ApoE^(−/−))mice were fed a high-fat and high-cholesterol diet for 3 months to establish atherosclerosis model.Meanwhile the mice were administered UroA(50 mg·kg−1·d−1,i.g.).We showed that UroA administration significantly decreased diet-induced atherosclerotic lesions in brachiocephalic arteries,macrophage content in plaques,expression of endothelial adhesion molecules,intraplaque hemorrhage and size of necrotic core,while increased the expression of smooth muscle actin and the thickness of fibrous cap,implying features of plaque stabilization.The underlying mechanisms were elucidated using TNF-α-stimulated human endothelial cells.Pretreatment with UroA(10,25,50μM)dose-dependently inhibited TNF-α-induced endothelial cell activation and monocyte adhesion.However,the anti-inflammatory effects of UroA in TNF-α-stimulated human umbilical vein endothelial cells(HUVECs)were independent of NF-κB p65 pathway.We conducted RNA-sequencing profiling analysis to identify the differential expression of genes(DEGs)associated with vascular function,inflammatory responses,cell adhesion and thrombosis in UroA-pretreated HUVECs.Human disease enrichment analysis revealed that the DEGs were significantly correlated with cardiovascular diseases.We demonstrated that UroA pretreatment mitigated endothelial inflammation by promoting NO production and decreasing YAP/TAZ protein expression and TEAD transcriptional activity in TNF-α-stimulated HUVECs.On the other hand,we found that UroA administration modulated the transcription and cleavage of lipogenic transcription factors SREBP1/2 in the liver to ameliorate cholesterol metabolism in ApoE^

关 键 词：atherosclerosis urolithin A INFLAMMATION YAP/TAZ endothelial cells 

分 类 号：R543.5[医药卫生—心血管疾病]