PMID- 34753029 OWN - NLM STAT- MEDLINE DCOM- 20211122 LR - 20211122 IS - 1618-095X (Electronic) IS - 0944-7113 (Linking) VI - 93 DP - 2021 Dec TI - Qing-Xue-Xiao-Zhi formula attenuates atherosclerosis by inhibiting macrophage lipid accumulation and inflammatory response via TLR4/MyD88/NF-kappaB pathway regulation. PG - 153812 LID - S0944-7113(21)00355-X [pii] LID - 10.1016/j.phymed.2021.153812 [doi] AB - BACKGROUND: Atherosclerosis is a progressive chronic disease characterised by aberrant lipid metabolism and a maladaptive inflammatory response. As atherosclerosis-driven cardiovascular disease remains the major cause of morbidity and mortality worldwide, more effective clinical therapies are urgently needed. Traditional Chinese Medicine (TCM) has demonstrated efficacy against atherosclerosis, with Qing-Xue-Xiao-Zhi formula (QXXZF) having been approved for clinical treatment of patients with atherosclerosis. However, the mechanisms underlying the anti-atherosclerotic activity of QXXZF remain unknown. PURPOSE: To investigate the anti-atherosclerotic effect of QXXZF and reveal its mechanisms using preclinical models. METHODS: In vivo, apolipoprotein E-deficient (ApoE(-/-)) mice were fed a high-fat and high-choline diet (HHD) to induce atherosclerosis. Serum metabolomic profiling was used to identify the concentration of trimethylamine N-oxide (TMAO) in mice. In vitro, RAW264.7 macrophages and bone marrow-derived macrophages (BMDMs) from WT and TLR4(-/-) C57BL/6 mice were used to explore the effects of QXXZF on macrophages. After confirming the therapeutic effects of QXXZF, mass spectrometry and network pharmacology analyses were used to predict and investigate the main components and the anti-atherogenic mechanisms of QXXZF in the context of atherosclerosis. RESULTS: Our results showed QXXZF significantly suppressed the development of atherosclerosis, as evidenced by the decreased atherosclerotic plaques in the aorta and aortic root, reduced plasma lipid levels and decreased serum TMAO content in HHD-fed ApoE(-/-) mice. Meanwhile, QXXZF effectively reduced foam cell formation in oxidized low-density lipoprotein (ox-LDL) and TMAO-stimulated RAW264.7 macrophages and BMDMs. Moreover, QXXZF facilitated reverse cholesterol transport (RCT) in macrophages by upregulating the expression of cholesterol efflux-related genes PPARgamma/LXRalpha/ABCA1/ABCG1. Mechanistic studies revealed that QXXZF influenced cholesterol metabolism by inhibiting the TLR4-mediated nuclear factor kappa B (NF-kappaB) axis. Importantly, TLR4 knockout abolished the influence of QXXZF on macrophages. CONCLUSION: QXXZF promotes lipid efflux and inhibits macrophage-mediated inflammation, producing a therapeutic effect against atherosclerosis. Our study provides new insight into the mechanism of QXXZF against atherosclerosis. CI - Copyright (c) 2021 Elsevier GmbH. All rights reserved. FAU - Li, Yue AU - Li Y AD - Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, 23 Backstreet of Art Gallery, Dongcheng District, Beijing 100010, China.; Beijing Institute of Traditional Chinese Medicine,23 Backstreet of Art Gallery, Dongcheng District, Beijing 100010, China. FAU - Zhang, Lei AU - Zhang L AD - Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, 23 Backstreet of Art Gallery, Dongcheng District, Beijing 100010, China.; Beijing Institute of Traditional Chinese Medicine,23 Backstreet of Art Gallery, Dongcheng District, Beijing 100010, China. FAU - Ren, Pan AU - Ren P AD - Weihai Hospital of Traditional Chinese Medicine, Shandong 264200, China. FAU - Yang, Yang AU - Yang Y AD - State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200031, China. FAU - Li, Sinai AU - Li S AD - Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, 23 Backstreet of Art Gallery, Dongcheng District, Beijing 100010, China.; Beijing Institute of Traditional Chinese Medicine,23 Backstreet of Art Gallery, Dongcheng District, Beijing 100010, China. FAU - Qin, Xiaomei AU - Qin X AD - Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, 23 Backstreet of Art Gallery, Dongcheng District, Beijing 100010, China.; Beijing Institute of Traditional Chinese Medicine,23 Backstreet of Art Gallery, Dongcheng District, Beijing 100010, China. FAU - Zhang, Meng AU - Zhang M AD - Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, 23 Backstreet of Art Gallery, Dongcheng District, Beijing 100010, China.; Beijing Institute of Traditional Chinese Medicine,23 Backstreet of Art Gallery, Dongcheng District, Beijing 100010, China. FAU - Zhou, Mingxue AU - Zhou M AD - Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, 23 Backstreet of Art Gallery, Dongcheng District, Beijing 100010, China.; Beijing Institute of Traditional Chinese Medicine,23 Backstreet of Art Gallery, Dongcheng District, Beijing 100010, China.. Electronic address: mingxue78@163.com. FAU - Liu, Weihong AU - Liu W AD - Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, 23 Backstreet of Art Gallery, Dongcheng District, Beijing 100010, China.; Beijing Institute of Traditional Chinese Medicine,23 Backstreet of Art Gallery, Dongcheng District, Beijing 100010, China.. Electronic address: wh.l-007@163.com. LA - eng PT - Journal Article DEP - 20211020 PL - Germany TA - Phytomedicine JT - Phytomedicine : international journal of phytotherapy and phytopharmacology JID - 9438794 RN - 0 (ATP Binding Cassette Transporter 1) RN - 0 (Apolipoproteins E) RN - 0 (Myd88 protein, mouse) RN - 0 (Myeloid Differentiation Factor 88) RN - 0 (NF-kappa B) RN - 0 (TLR4 protein, human) RN - 0 (Tlr4 protein, mouse) RN - 0 (Toll-Like Receptor 4) SB - IM MH - ATP Binding Cassette Transporter 1 MH - Animals MH - Apolipoproteins E/genetics MH - *Atherosclerosis/drug therapy MH - Humans MH - Macrophages/metabolism MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Myeloid Differentiation Factor 88 MH - *NF-kappa B/metabolism MH - Toll-Like Receptor 4/metabolism OTO - NOTNLM OT - Atherosclerosis OT - Inflammation OT - Lipid metabolism OT - Macrophages OT - Traditional Chinese Medicine EDAT- 2021/11/10 06:00 MHDA- 2021/11/23 06:00 CRDT- 2021/11/09 20:17 PHST- 2021/05/26 00:00 [received] PHST- 2021/10/01 00:00 [revised] PHST- 2021/10/17 00:00 [accepted] PHST- 2021/11/10 06:00 [pubmed] PHST- 2021/11/23 06:00 [medline] PHST- 2021/11/09 20:17 [entrez] AID - S0944-7113(21)00355-X [pii] AID - 10.1016/j.phymed.2021.153812 [doi] PST - ppublish SO - Phytomedicine. 2021 Dec;93:153812. doi: 10.1016/j.phymed.2021.153812. Epub 2021 Oct 20.