Mechanism of Huayu Qutan recipe (化瘀祛痰方) anti-atherosclerosis mediates lipophagy via mammalian target of rapamycin complex 1/ transcription factor EB signaling pathway in ApoE-/-mice

doi:10.19852/j.cnki.jtcm.2025.02.016

Journal of Traditional Chinese Medicine ›› 2025, Vol. 45 ›› Issue (2): 291-302.DOI: 10.19852/j.cnki.jtcm.2025.02.016

• Original articles • Previous Articles Next Articles

Mechanism of Huayu Qutan recipe (化瘀祛痰方) anti-atherosclerosis mediates lipophagy via mammalian target of rapamycin complex 1/ transcription factor EB signaling pathway in ApoE-/-mice

LI Yue¹^,², PAN Jiaxiang¹, YANG Guanlin³, YU Jiajia⁴, WU Xize⁵, MIN Dongyu⁶, CHENG Meijia⁶, YU Dongdong⁷, NAN Minghua⁸^,⁹, GAO Xiaoyu¹⁰, PANG Linlin¹, GONG Lihong¹^,²(), JIA Lianqun³()

1 Department of Cardiology, the Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang 110032, China
2 Liaoning Provincial Key Laboratory of TCM Geriatric Cardio-Cerebrovascular Diseases, Shenyang 110032, China
3 Innovation Engineering Technology Center of Traditional Chinese Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang 110847, China
4 Postdoctoral Program of Liaoning University of Traditional Chinese Medicine, Shenyang 110847, China
5 Graduate School of Liaoning University of Traditional Chinese Medicine, Shenyang 110847, China
6 Experimental Center of Traditional Chinese Medicine, the Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang 110032, China
7 Department of Osteology, Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang 110032, China
8 Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications of Liaoning University of Traditional Chinese Medicine, Shenyang 110847, China
9 Second Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang 110000, China
10 Department of Oncology department, Shengjing Hospital affiliated to China Medical University, Shenyang 110000, China

Received:2023-12-12 Accepted:2024-05-15 Online:2025-04-15 Published:2025-03-10
Contact: Prof. JIA Lianqun, Department of Academic Affairs Office, Liaoning University of Traditional Chinese Medicine, Shenyang 110847, China. jlq-8@163.com; Prof. GONG Lihong, Department of Cardiology, Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang 110032, China. 215922524@qq.com, Telephone: +86-24-82961157
Supported by:
Science and Technology Research Project of Education Department of Liaoning Province: the Mechanism of Regulating Lipophagy and Affecting Cholesterol Efflux in Human Promyelocytic Leukemia Cell Line Macrophages by Huayu Qutan Recipe based on the Theory of "Laoxia Shengtan"(L202048);Youth Project of Basic Scientific Research Project of Education Department of Liaoning Province: Mechanism of Mitochondrial Autophagy and Apoptosis in L02 Hepatocytes Regulated by miR-7043-3p based on the Theory of "Spleen Qi Dispersing Essence" of Huayu Qutan Recipe(LJKQZ2021064)

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Abstract

Abstract:

OBJECTIVE: To investigate the effects of Huayu Qutan recipe (化瘀祛痰方, HYQT) on the atherosclerosis (AS) model of ApoE-/- mice with a high-fat diet and to illustrate the underlying mechanisms from modern patho-physiological conceptualizations.

METHODS: High performance liquid chromatography of quadrupole time of flight-tandem mass spectrometry (HPLC-Q-TOF-MS/MS) analysis was used to identify the active compounds in the recipe. The mice were randomly allocated into 7 groups: control (CTRL) group, normal diet (ND) group, high-fat diet (HFD) group, HYQT groups (low dose, medium dose, and high dose), and simvastatin (SIM) group. Deferent doses of HYQT were gavaged twice a day, and then the protective effect of HYQT on plaque formation in ApoE-/- mice with a high-fat diet was verified viahematoxylin-eosin (HE) staining and oil red o (ORO) staining. We observed the co-localization in aortic macrophages and lipid droplets (LDs) by CD68 and the Bodipy fluorescence probe. Light chain 3 phosphoprotein class Ⅱ/light chain 3 phosphoprotein class Ⅰ (LC3Ⅱ/LC3Ⅰ) was examined by western blotting, and sequestosome 1 (SQSTM1/p62), Beclin1, Lamp1, mammalian target of rapamycin (mTOR), phosphorylated mammalian target of rapamycin (p-mTOR), and ATP-binding cassette transporter A1 (ABCA1) were examined by real-time polymerase chain reaction (RT-PCR) and Western blotting. Transcription factor EB (TFEB) nuclear translocation was determined by immunofluorescence analysis.

RESULTS: Five active compounds were identified using HPLC-Q-TOF-MS/MS analysis: ferulic acid, chlorogenic acid, calycosin, formononetin, and 8,2'-dihydroxy-7,4'-dimethoxy-isoflavane. The effect of HYQT on atherosclerotic plaque formation in ApoE-/- mice was investigated. These findings showed that HYQT decreased the co-localization of CD68 and Bodipy and increased the co-localization of CD68 and LC3B. Medium and high doses of HYQT increased autophagosome formation and promoted the maturation of LC3Ⅱ/LC3Ⅰ. Additionally, HYQT decreased the expression of SQSTM1/p62. Medium and high doses of HYQT also increased the expression of Beclin1 and Lamp1. RT-PCR and Western blot results suggested that HYQT enhanced the expression of ABCA1 mRNA and protein and regulated the mTORC1/TFEB signaling pathway.

CONCLUSION: The results indicate that HYQT is an effective traditional Chinese herbal remedy for the treatment of AS. HYQT mitigates macrophage-derived foam cell formation by activating autophagy in atherosclerosis. The mTOR/TFEB signaling pathway and ABCA1 are therapeutic targets of HYQT for the treatment of AS.

Key words: atherosclerosis, foam cells, lipid metabolism, diet, high-fat, Huayu Qutan recipeSupporting information

LI Yue, PAN Jiaxiang, YANG Guanlin, YU Jiajia, WU Xize, MIN Dongyu, CHENG Meijia, YU Dongdong, NAN Minghua, GAO Xiaoyu, PANG Linlin, GONG Lihong, JIA Lianqun. Mechanism of Huayu Qutan recipe (化瘀祛痰方) anti-atherosclerosis mediates lipophagy via mammalian target of rapamycin complex 1/ transcription factor EB signaling pathway in ApoE-/-mice[J]. Journal of Traditional Chinese Medicine, 2025, 45(2): 291-302.

Figures/Tables 5

Figure 1 The extracted ion chromatograms of HYQT A: the extracted ion chromatograms of HYQT. A1: the total ion flow diagram of UPLC-Q/TOF-MS negative-ion mode of mixed standards; A2: the total ion flow diagram of UPLC-Q/TOF-MS negative-ion mode of HYQT sample; A3: the total ion flow diagram of UPLC-Q/TOF-MS positive-ion mode of mixed standards; A4: the total ion flow diagram of UPLC-Q/TOF-MS positive-ion mode of HYQT sample; P1: Ferulic acid; P2: Chlorogenic acid; P3: Calyx isoflavone; P4: Formononetin; P5: 8,2 '-dihydroxy-7,4' -dimethoxy-isoflavane. HYQT: Huayu Qutan recipe; UPLC-Q/TOF-MS: high performance liquid chromatography of quadrupole time of flight-tandem mass spectrometry.

Table 1 Mice were weighted weekly for the 7 groups

Time	n	CTRL	ND	HFD	L-HYQT	M-HYQT	H-HYQT	SIM
0 week	10	17.50±0.90	17.3±0.96	17.4±0.56	17.23±1.15	17.23±0.35	17.73±0.23	17.46±0.70
4 weeks	10	20.13±1.36	20.73±1.30	22.00±0.87	20.97±1.19	20.33±1.15	20.67±1.27	20.97±1.31
8 weeks	10	22.47±1.60	23.13±2.11	25.73±0.67^ab	24.63±1.94^cd	24.67±0.58^cd	23.94±1.46	24.70±1.62
12 weeks	10	25.20±0.96	25.63±0.75	29.47±0.40^ab	28.27±0.51^ab	28.21±0.71^cd	27.28±0.93^bc	27.52±1.37^cde
16 weeks	10	27.67±0.50	27.73±0.40	33.60±1.14^ab	32.93±0.67^ab	30.93±0.59^abf	30.80±0.40^abdfg	30.80±1.40^abdfg

Figure 2 Effects of HYQT on atherosclerosis ORO and HE staining were performed. A: full-length aorta containing most of the thoracic aorta, and abdominal aorta with ORO staining; B: image analysis of ORO (n = 3 per group). C: HE stains of aortas (Scale bar: 50 μm), C1-C7: Pathological changes of aorta of CTRL, ND, HFD, L-HYQT, M-HYQT, H-HYQT, and SIM group in week 16. D: ORO stains of aortas (Scale bar: 50 μm), D1-D7: ORO stains of CTRL, ND, HFD, L-HYQT, M-HYQT, H-HYQT, and SIM group in week 16. CTRL group: C57/BL6J mice, normal diet for 16 weeks; ND group: ApoE-/- mice, normal diet for 16 weeks; HFD group: ApoE-/- mice, HFD for 16 weeks; L-HYQT group: ApoE-/- mice, HFD for 16 weeks and received HYQT for 8 weeks (10.27 g·kg-1·d-1); M-HYQT group: ApoE-/- mice, HFD for 16 weeks, received HYQT for 8 weeks (20.54 g·kg-1·d-1); H-HYQT group: ApoE-/- mice, HFD for 16 weeks, received HYQT for 8 weeks (41.08 g·kg-1·d-1); SIM group: ApoE-/- mice, HFD for 16 weeks, received SIM for 8 weeks (10 mg·kg-1·d-1). ORO: oil red O; HE: hematoxylin-eosin; CTRL: control; ND: normal diet; HFD: high fat diet; HYQT: Huayu Qutan recipe; L-HYQT: low dose of Huayu Qutan recipe; M-HYQT: middle dose of Huayu Qutan recipe; H-HYQT: high dose of Huayu Qutan recipe; ANOVA: one-way analysis of variance; SEM: standard error of mean. ANOVA was performed for normal distribution data. The data were presented as the mean ± SEM from 3 independent experiments. aP < 0.01 vs ND group, bP < 0.05 vs HFD group, cP < 0.05 vs L-HYQT group.

Figure 3 HYQT promoted lipophagy in aortic tissue A: fluorescence images of CD68-LC3B in aortic root sections obtained from mice in week 16 (scale bar: 50 μm). A1-A3: CD68-LC3B in aortic root of CTRL group; A4-A6: CD68-LC3B in aortic root of ND group; A7-A9: CD68-LC3B in aortic root of HFD group; A10-A12: CD68-LC3B in aortic root of L-HYQT; A13-A15: CD68-LC3B in aortic root of M-HYQT group; A16-A18: CD68-LC3B in aortic root of H-HYQT group; A19-A21: CD68-LC3B in aortic root of SIM group. B: TEM image of 1 μm (the yellow arrow points to the lysosome and the yellow star locats lipophagy, scale bar: 2.0 μm). B: the formation of autophagosomes and lipid droplets was observed by transmission electron microscopy in week 16. B1: CTRL group; B2: ND group; B3: HFD group; B4: L-HYQT group; B5: M-HYQT group; B6: H-HYQT group; B7: SIM group. CTRL group: C57/BL6J mice, normal diet for 16 weeks; ND group: ApoE-/- mice, normal diet for 16 weeks; HFD group: ApoE-/- mice, HFD for 16 weeks; L-HYQT group: ApoE-/- mice, HFD for 16 weeks and received HYQT for 8 weeks (10.27 g·kg-1·d-1); M-HYQT group: ApoE-/- mice, HFD for 16 weeks, received HYQT for 8 weeks (20.54 g·kg-1·d-1); H-HYQT group: ApoE-/- mice, HFD for 16 weeks, received HYQT for 8 weeks (41.08 g·kg-1·d-1); SIM group: ApoE-/- mice, HFD for 16 weeks, received SIM for 8 weeks (10 mg·kg-1·d-1). CTRL: control; ND: normal diet; HFD: high fat diet; HYQT: Huayu Qutan recipe; L-HYQT: low dose of Huayu Qutan recipe; M-HYQT: middle dose of Huayu Qutan recipe; H-HYQT: high dose of Huayu Qutan recipe; SIM: simvastatin; CD68: macrophage Antigen CD68; LC3B: Microtubule-associated protein 1 light chain 3 beta; TEM: transmission electron microscopy.

Figure 4 HYQT regulated lipophagy through the mTORC1/TFEB signaling pathway, and ABCA1 genes and proteins expression in aortic. A: the expression level of Beclin1 mRNA; B: the expression level of p62 mRNA; C: the expression level of Lamp1 mRNA. The data were detected by reverse transcription PCR (RT-PCR) of aortic in week 16; D: the expression level of LC3A/B, Beclin1, p62 and Lamp1 were determined by Western blotting, using β‐actin as a loading control; E: Western blot analysis of LC3 A/B; F: Western blot analysis of Beclin1;G: Western blot analysis of p62; H: Western blot analysis of Lamp1; I: mTOR, p-mTOR, ABCA1 expression detected by Western blot; J: relative expression level of mTOR protein; K: p-mTOR protein; L: p-mTOR/mTOR protein; M: the expression level of ABCA1 mRNA; N: the expression level of ABCA1 protein. CTRL group: C57/BL6J mice, normal diet for 16 weeks; ND group: ApoE-/- mice, normal diet for 16 weeks; HFD group: ApoE-/- mice, HFD for 16 weeks; L-HYQT group: ApoE-/- mice, HFD for 16 weeks and received HYQT for 8 weeks (10.27 g·kg-1·d-1); M-HYQT group: ApoE-/- mice, HFD for 16 weeks, received HYQT for 8 weeks (20.54 g·kg-1·d-1); H-HYQT group: ApoE-/- mice, HFD for 16 weeks, received HYQT for 8 weeks (41.08 g·kg-1·d-1); SIM group: ApoE-/- mice, HFD for 16 weeks, received SIM for 8 weeks (10 mg·kg-1·d-1). Beclin1: recombinant beclin 1; p62: sequestosome 1??; mTORC1: mechanistic target of rapamycin complex 1; p-mTOR: phosphorylated mammalian target of rapamycin; Lamp1: recombinant lysosomal associated membrane protein 1; LC3 A/B: autophagy related protein LC3 A/B; ABCA1: ATP-binding cassette transporter A1; ANOVA: one-way analysis of variance; SEM: standard error of mean. ANOVA was performed for normal distribution data. The data were presented as the mean ± SEM from 3 independent experiments. aP < 0.01, eP < 0.05, vs HFD group; bP < 0.01, fP < 0.05, vs L-HYQT group; cP < 0.01 vs CTRL group, dP < 0.01, gP < 0.05, vs ND group.

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Mechanism of Huayu Qutan recipe (化瘀祛痰方) anti-atherosclerosis mediates lipophagy via mammalian target of rapamycin complex 1/ transcription factor EB signaling pathway in ApoE-/-mice

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