The combination of EGCG with warfarin reduces deep vein thrombosis in rabbits through modulating HIF-1αand VEGF via the PI3K/AKT and ERK1/2 signaling pathways
作者机构：Department of Vascular and Interventional RadiologyNanjing First HospitalNanjing Medical UniversityNanjing 210006China Department of AcupunctureQinhuai District Hospital of Traditional Chinese MedicineNanjing 210000China
出 版 物：《Chinese Journal of Natural Medicines》 (中国天然药物（英文版）)
年 卷 期：2022年第20卷第9期
页 面：679-690页
核心收录：
学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 1002[医学-临床医学] 10[医学] 100602[医学-中西医结合临床]
基 金：supported by the National Nature Science Foundation of China(No.81871463) Nanjing Health Science and Technology Development Special Fund Project(No.YKK19086).
主 题：Deep vein thrombosis EGCG Warfarin HIF-1α VEGF PI3K/AKT ERK1/2
摘 要：Deep venous thrombosis(DVT)poses a major challenge to public health worldwide.Endothelial cell injury evokes inflammatory and oxidative responses that contribute to thrombus formation.Tea polyphenol(TP)in the form of epigallocatechin-3-gallate(EGCG)has anti-inflammatory and oxidative effect that may ameliorate DVT.However,the precise mechanism remains incompletely understood.The current study was designed to investigate the anti-DVT mechanism of EGCG in combination with warfarin(an oral anticoagulant).Rabbits were randomly divided into five groups.A DVT model of rats was established through ligation of the inferior vena cava(IVC)and left common iliac vein,and the animals were orally administered with EGCG,warfarin,or vehicle for seven days.In vitro studies included pretreatment of human umbilical vein endothelial cells(HUVECs)with different concentrations of EGCG for 2 h before exposure to hydrogen peroxide.Thrombus weight and length were examined.Histopathological changes were observed by hematoxylin-eosin staining.Blood samples were collected for detecting coagulation function,including thrombin and prothrombin times,activated partial thromboplastin time,and fibrinogen levels.Protein expression in thrombosed IVCs and HUVECs was evaluated by Western blot,immunohistochemical analysis,and/or immunofluorescence staining.RT-qPCR was used to determine the levels of AGTR-1 and VEGF mRNA in IVCs and HUVECs.The viability of HUVECs was examined by CCK-8 assay.Flow cytometry was performed to detect cell apoptosis and ROS generation was assessed by 2′,7ʹ-dichlorofluorescein diacetate reagent.In vitro and in vivo studies showed that EGCG combined with warfarin significantly reduced thrombus weight and length,and apoptosis in HUVECs.Our findings indicated that the combination of EGCG and warfarin protects HUVECs from oxidative stress and prevents apoptosis.However,HIF-1αsilencing weakened these effects,which indicated that HIF-1αmay participate in DVT.Furthermore,HIF-1αsilencing significantly up-regulated cell apoptosis and ROS generation,and enhanced VEGF expression and the activation of the PI3K/AKT and ERK1/2 signaling pathways.In conclusion,our results indicate that EGCG combined with warfarin modifies HIF-1αand VEGF to prevent DVT in rabbits through anti-inflammation via the PI3K/AKT and ERK1/2 signaling pathways.
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