河北医学2024，Vol.30Issue(6)：892-899,8.DOI:10.3969/j.issn.1006-6233.2024.06.03
肠道菌群代谢产物氧化三甲胺通过抑制Keap1/Nrf2信号通路激活发挥促动脉粥样硬化作用
Gut Microbiota Metabolite Trimethylamine N-oxide Promotes Atherosclerosis by Inhibiting the Keap1/Nrf2 Signaling Pathway
摘要
Abstract
Objective:To investigate the effects of the gut microbiota(GM)metabolite trimethylamine N-oxide(TMAO)on atherosclerosis(AS)and its related mechanisms.Methods:Male mice were randomly di-vided into the control group,model group,TMAO group,Keap1/Nrf2 activator RTA-408 group,and TMAO+RTA-408 group,with 12 mice in each group.The model group mice were fed a high-fat diet,while the TMAO group mice were fed a high-fat diet with 1%choline for a modeling period of 12 weeks.After model-ing,mice in the RTA-408 and TMAO+RTA-408 groups received a single daily intraperitoneal injection of RTA-408(100 μg/kg)for 14 days,while mice in other groups received equivalent amounts of saline.Bio-chemical analysis was used to quantify the levels of TG,TC,LDL-C,and HDL-C.Histological changes in the aorta were detected using HE,Masson trichrome,and oil red O staining.ELISA was used to detect serum levels of interleukin-1β(IL-1β),reactive oxygen species(ROS),and superoxide dismutase(SOD).Ultra-high performance liquid chromatography-tandem mass spectrometry(UHPLC-MS/MS)was used to detect plasma TMAO levels in mice.Fluorescent probe assays were used to detect ROS fluorescence intensity in the aorta.qRT-PCR and Western blot were used to detect mRNA and protein expression levels of Keap1,Nrf2,and HO-1 in mouse aortic tissue.Immunofluorescence was used to observe Nrf2 nuclear translocation.Re-sults:Serum TC,TG,and LDL-C concentrations were higher in AS mice compared to the control group,while HDL-C concentration was lower(P<0.01).Additionally,the model group showed extensive aortic inti-ma thickening,significant foam cell formation,and increased collagen deposition in the arterial wall.Serum levels of IL-1β,ROS,and TMAO were significantly elevated(P<0.01),while SOD activity was significant-ly reduced(P<0.01).Aortic ROS content increased,Nrf2 nuclear translocation was significantly inhibited(P<0.01),and mRNA and protein expression levels of Keap1,Nrf2,and HO-1 increased(P<0.01).Compared to AS mice,TMAO treatment further aggravated the changes in these indicators(P<0.05);RTA-408,however,negated the exacerbating effects of TMAO on AS mice(P<0.05).Conclusion:TMAO may exacerbate aortic pathological changes,inflammatory responses,and endothelial injury in AS mice by inhibi-ting the activation of the Keap1/Nrf2 signaling pathway.关键词
动脉粥样硬化/肠道菌群代谢产物/氧化三甲胺/Keap1/Nrf2信号通路Key words
Atherosclerosis/Gut microbiome metabolites/Trimethylamine-N-oxide/Keap1/Nrf2 signaling pathway引用本文复制引用
单思阳,郭凡,杨浩,马洁,张裕祥..肠道菌群代谢产物氧化三甲胺通过抑制Keap1/Nrf2信号通路激活发挥促动脉粥样硬化作用[J].河北医学,2024,30(6):892-899,8.基金项目
新疆维吾尔自治区卫生健康委员会青年项目,(编号:WJWY-XCZX202217) （编号:WJWY-XCZX202217）
