Shikonin attenuates hyperhomocysteinemia-induced CD4+ T cell inflammatory activation and atherosclerosis in ApoE-/- mice by metabolic suppression
Shikonin attenuates hyperhomocysteinemia-induced CD4+ T cell inflammatory activation and atherosclerosis in ApoE-/- mice by metabolic suppression
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Shikonin 通过代谢抑制来减轻 ApoE-/- 小鼠中高同型半胱氨酸血症诱导的 CD4 T 细胞炎症激活和动脉粥样硬化。
DOI：
10.1038/s41401-019-0308-7
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发表时间：
2020-01-01
影响因子：
8.2
通讯作者：
Feng, Juan
中科院分区：
文献类型：
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作者：
Lu, Si-lin;Dang, Guo-hui;Feng, Juan
T细胞代谢激活在动脉粥样硬化炎症中起着至关重要的作用。紫草素（SKN）是一种具有抗炎活性的天然萘醌，已被证明具有心脏保护作用，但其对动脉粥样硬化的作用尚不清楚。此外，SKN通过靶向丙酮酸激酶肌同工酶2 （PKM2）抑制糖酵解。在本研究中，我们研究了SKN对ApoE（-/-）小鼠高同型半胱氨酸血症（HHcy）加速动脉粥样硬化和T细胞炎症激活的影响及其代谢机制。给ApoE（-/-）小鼠补充Hcy （1.8g/L）的饮用水2周，每3天给小鼠注射SKN （1.2mg/kg, ig）或载药。我们发现，SKN治疗可显著减轻ApoE（-/-）小鼠的hhcy加速动脉粥样硬化，并显著降低斑块中炎症激活的CD4(+) T细胞和促炎巨噬细胞。在从HHcy-ApoE（-/-）小鼠分离的脾CD4(+) T细胞中，SKN处理显著抑制hhcy刺激的PKM2活性、干扰素γ分泌以及这些T细胞促进巨噬细胞促炎极化的能力。SKN处理显著抑制hhcy刺激的CD4(+) T细胞糖酵解和氧化磷酸化。CD4(+) T细胞的代谢谱分析显示，Hcy给药显著增加了各种葡萄糖代谢物、脂质和乙酰辅酶a羧化酶1，SKN治疗可逆转这一现象。总之，我们的研究结果表明，SKN可以有效改善HHcy-ApoE（-/-）小鼠的动脉粥样硬化，这至少部分与SKN通过pkm2依赖性代谢抑制对CD4(+) T细胞炎症激活的抑制有关。
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 (1.8g/L) was administered to ApoE(-/-) mice for 2 weeks and the mice were injected with SKN (1.2mg/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-gamma 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.