Shikonin attenuates hyperhomocysteinemia-induced CD4+ T cell inflammatory activation and atherosclerosis in ApoE-/-mice by metabolic suppression

• 来源期刊: 中国药理学报（英文版）
• 关键词: atherosclerosis shikonin naphthoquinone hyperhomocysteinemia CD4+ T cell metabolic suppression ApoE-/-mice
• 年，卷（期）: 2020,（1）
• 页码范围: 47-55
• 页数: 9页
• 语种: 英文

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-y secretion 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.