Shikonin attenuates hyperhomocysteinemia-induced CD4E^+T cell inflammatory activation and atherosclerosis in ApoE^−/− mice by metabolic suppression  

作　　者：Si-lin Lü Guo-hui Dang Jia-cheng Deng Hui-ying Liu Bo Liu Juan Yang Xiao-long Ma Yu-tong Miao Chang-tao Jiang Qing-bo Xu Xian Wang Juan Feng 

机构地区：[1]Department of Physiology and Pathophysiology,School of Basic Medical Sciences,Peking University Health Science Center,Key Laboratory of Molecular Cardiovascular Science,Ministry of Education,Beijing 100191,China [2]State Key Laboratory of Bioactive Substances and Function of Natural Medicine,Institute of Materia Medica,Peking Union Medical College,Chinese Academy of Medical Sciences,Beijing 100050,China [3]Cardiovascular Division,BHF Centre for Vascular Regeneration,King’s College London,London SE59NU,UK [4]Department of Integration of Chinese and Western Medicine,School of Basic Medical Sciences,Peking University,Beijing 100191,China

出　　处：《Acta Pharmacologica Sinica》2020年第1期47-55,共9页中国药理学报（英文版）

基　　金：the National Natural Science Foundation of China(Nos.91739303,81770445).

摘　　要：T cell metabolic activation plays a crucial role in inflammation of atherosclerosis.Shikonin(SKN),a natural naphthoquinone with anti-inflammatory activity,has shown to exert cardioprotective effects,but the effect of SKN on atherosclerosis is unclear.In addition,SKN was found to inhibit glycolysis via targeting pyruvate kinase muscle isozyme 2(PKM2).In the present study,we investigated the effects of SKN on hyperhomocysteinemia(HHcy)-accelerated atherosclerosis and T cell inflammatory activation in ApoE^−/− mice and the metabolic mechanisms in this process.Drinking water supplemented with Hcy(1.8 g/L)was administered to ApoE^−/− mice for 2 weeks and the mice were injected with SKN(1.2 mg/kg,i.p.)or vehicle every 3 days.We showed that SKN treatment markedly attenuated HHcy-accelerated atherosclerosis in ApoE^−/− mice and significantly decreased inflammatory activated CD4^+T cells and proinflammatory macrophages in plaques.In splenic CD4^+T cells isolated from HHcy-ApoE^−/− mice,SKN treatment significantly inhibited HHcy-stimulated PKM2 activity,interferon-γsecretion and the capacity of these T cells to promote macrophage proinflammatory polarization.SKN treatment significantly inhibited HHcy-stimulated CD4^+T cell glycolysis and oxidative phosphorylation.Metabolic profiling analysis of CD4^+T cells revealed that Hcy administration significantly increased various glucose metabolites as well as lipids and acetyl-CoA carboxylase 1,which were reversed by SKN treatment.In conclusion,our results suggest that SKN is effective to ameliorate atherosclerosis in HHcy-ApoE^−/− mice and this is at least partly associated with the inhibition of SKN on CD4^+T cell inflammatory activation via PKM2-dependent metabolic suppression.

关 键 词：ATHEROSCLEROSIS SHIKONIN NAPHTHOQUINONE HYPERHOMOCYSTEINEMIA CD4^+T cell metabolic suppression ApoE^−/−mice 

分 类 号：R73[医药卫生—肿瘤]