PMID- 31607752 OWN - NLM STAT- MEDLINE DCOM- 20201001 LR - 20220420 IS - 1745-7254 (Electronic) IS - 1671-4083 (Print) IS - 1671-4083 (Linking) VI - 41 IP - 1 DP - 2020 Jan TI - Shikonin attenuates hyperhomocysteinemia-induced CD4(+) T cell inflammatory activation and atherosclerosis in ApoE(-/-) mice by metabolic suppression. PG - 47-55 LID - 10.1038/s41401-019-0308-7 [doi] AB - 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-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. FAU - Lu, Si-Lin AU - Lu SL AD - 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. AD - 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. FAU - Dang, Guo-Hui AU - Dang GH AD - 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. FAU - Deng, Jia-Cheng AU - Deng JC AD - 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. FAU - Liu, Hui-Ying AU - Liu HY AD - 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. FAU - Liu, Bo AU - Liu B AD - 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. FAU - Yang, Juan AU - Yang J AD - 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. FAU - Ma, Xiao-Long AU - Ma XL AD - 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. FAU - Miao, Yu-Tong AU - Miao YT AD - 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. FAU - Jiang, Chang-Tao AU - Jiang CT AD - 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. FAU - Xu, Qing-Bo AU - Xu QB AD - Cardiovascular Division, BHF Centre for Vascular Regeneration, King's College London, London, SE5 9NU, UK. FAU - Wang, Xian AU - Wang X AD - 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. xwang@bjmu.edu.cn. FAU - Feng, Juan AU - Feng J AD - 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. juanfeng@bjmu.edu.cn. AD - Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, 100191, China. juanfeng@bjmu.edu.cn. LA - eng PT - Journal Article DEP - 20191013 PL - United States TA - Acta Pharmacol Sin JT - Acta pharmacologica Sinica JID - 100956087 RN - 0 (Anti-Inflammatory Agents, Non-Steroidal) RN - 0 (Apolipoproteins E) RN - 0 (Naphthoquinones) RN - 3IK6592UBW (shikonin) SB - IM MH - Animals MH - Anti-Inflammatory Agents, Non-Steroidal/administration & dosage/*pharmacology MH - Apolipoproteins E/*deficiency/genetics/metabolism MH - Atherosclerosis/*drug therapy/metabolism MH - CD4-Positive T-Lymphocytes/drug effects/metabolism MH - Dose-Response Relationship, Drug MH - Female MH - Hyperhomocysteinemia/*drug therapy/metabolism MH - Inflammation/*drug therapy/metabolism MH - Injections, Intraperitoneal MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Naphthoquinones/administration & dosage/*pharmacology PMC - PMC7468273 OTO - NOTNLM OT - ApoE-/- mice OT - CD4+ T cell OT - atherosclerosis OT - hyperhomocysteinemia OT - metabolic suppression OT - naphthoquinone OT - shikonin COIS- The authors declare no competing interests. EDAT- 2019/10/15 06:00 MHDA- 2020/10/02 06:00 PMCR- 2021/01/01 CRDT- 2019/10/15 06:00 PHST- 2019/06/17 00:00 [received] PHST- 2019/09/06 00:00 [accepted] PHST- 2019/10/15 06:00 [pubmed] PHST- 2020/10/02 06:00 [medline] PHST- 2019/10/15 06:00 [entrez] PHST- 2021/01/01 00:00 [pmc-release] AID - 10.1038/s41401-019-0308-7 [pii] AID - 308 [pii] AID - 10.1038/s41401-019-0308-7 [doi] PST - ppublish SO - Acta Pharmacol Sin. 2020 Jan;41(1):47-55. doi: 10.1038/s41401-019-0308-7. Epub 2019 Oct 13.