“气经-血络”截断动脉粥样硬化斑块形成：降脂化斑方调控小鼠肝脏逆向胆固醇转运途径改善动脉粥样硬化的机制

doi:10.12122/j.issn.1673-4254.2025.09.02

南方医科大学学报 ›› 2025, Vol. 45 ›› Issue (9): 1818-1829.doi: 10.12122/j.issn.1673-4254.2025.09.02

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“气经-血络”截断动脉粥样硬化斑块形成：降脂化斑方调控小鼠肝脏逆向胆固醇转运途径改善动脉粥样硬化的机制

王宏杨¹^,²(), 朱文怡¹, 陈栩燊¹, 张童¹, 曹志伟³, 王金³, 解渤³, 刘强², 任雪峰¹^,³()

^1.浙江中医药大学公共卫生学院，浙江杭州 310053
^2.浙江省中医院心血管科，浙江杭州 310053
^3.浙江中医药大学-苏州重生医药联合实验室，浙江杭州 310053

收稿日期:2025-04-01 出版日期:2025-09-20 发布日期:2025-09-28
通讯作者: 任雪峰 E-mail:wanghongyang0108@163.com;20231135@zcmu.edu.cn
作者简介:王宏杨，博士，在站博士后，E-mail: wanghongyang0108@163.com
基金资助:
浙江中医药大学校级科研项目(2023RCZXZK12);浙江省中医药科技计划项目(2025ZR106)

Disrupting atherosclerotic plaque formation via the "qi meridian-blood channel": mechanism of Jiangzhi Huaban Decoction for regulating hepatic reverse cholesterol transport to improve atherosclerosis

Hongyang WANG¹^,²(), Wenyi ZHU¹, Xushen CHEN¹, Tong ZHANG¹, Zhiwei CAO³, Jin WANG³, Bo XIE³, Qiang LIU², Xuefeng REN¹^,³()

^1.School of Public Health, Zhejiang Chinese Medical University, Hangzhou 310053, China
^2.Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou 310053, China
^3.Zhejiang Chinese Medical University-Suzhou Chongsheng Medicine Joint Laboratory, Hangzhou 310053, China

Received:2025-04-01 Online:2025-09-20 Published:2025-09-28
Contact: Xuefeng REN E-mail:wanghongyang0108@163.com;20231135@zcmu.edu.cn

摘要/Abstract

摘要：

目的在“气经-血络”的病理演变路径上，探究降脂化斑方（JZHB）改善动脉粥样硬化（AS）斑块的作用及其机制。方法 C57BL/6小鼠给予普通饲料作为空白对照组；将ApoE^-/-基因敲除小鼠给予高脂饲料联合喂养8周后随机分为模型组，JZHB低、中、高剂量组及阿托伐他汀钙组，8只/组，药物干预8周。每周记录小鼠体质量及一般情况，干预结束后取材，采用全自动生化分析仪检测小鼠血清中的甘油三酯、总胆固醇、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇、总胆汁酸、丙氨酸氨基转移酶和天冬氨酸氨基转移酶含量；采用油红O染色观察肝脏、主动脉脂质积聚情况；采用苏木素-伊红染色观察小鼠肝脏及主动脉根部的病理变化情况；采用转录组学测序技术分析其核心分子机制，并通过Western blotting、免疫组化检测核心机制靶标蛋白表达情况。结果 JZHB可降低AS小鼠血脂、总胆汁酸含量水平（P<0.05），改善肝功能损伤、脂肪变性及脂质沉积水平（P<0.05），减少主动脉脂质沉积及斑块面积（P<0.05）。转录组学分析显示，其机制与调控胆固醇逆向转运、炎症信号通路密切相关。动物实验结果显示，JZHB可上调小鼠肝脏中PPARγ、LXRα、ABCA1、ABCG1、CYP7A1蛋白表达（P<0.05），下调肝脏中p-NF-κB/NF-κB磷酸化比值、IL-6、IL-1β蛋白表达（P<0.05），上调肠道中ABCG5、ABCG8蛋白表达（P<0.05），并降低主动根斑块内ICAM-1、VCAM-1蛋白表达（P<0.05）。结论 JZHB能综合改善AS小鼠病变，其核心机制可能通过调控肝脏PPARγ/LXRα/NF-κB信号通路，改善肝脏胆固醇逆向转运及炎症水平，进而改善AS血管的脂质沉积损伤及斑块形成。

关键词: 动脉粥样硬化, 气经-血络, 降脂化斑方, 胆固醇逆向转运, 血管细胞黏附分子

Abstract:

Objective To explore the molecular mechanism of Jiangzhi Huaban Decoction (JZHBD) for improving atherosclerosis through the "qi meridian-blood channels" pathway. Methods ApoE^-/- mouse models of atherosclerosis were established by high-fat diet feeding for 8 weeks, with C57BL/6 mice on a normal diet as the controls. Forty ApoE^-/- mouse models were randomized into model group, low-, medium-, and high-dose JZHBD treatment groups, and atorvastatin treatment group (n=8) for their respective treatments for 8 weeks. The changes in body weight and overall condition of the mice were monitored weekly. After the treatments, serum levels of TC, TG, HDL-C, LDL-C, TBA, ALT, and AST of the mice were measured, pathological changes in the liver and aortic root plaques were examined with HE staining, and lipid accumulation in the liver and aortic wall was assessed using Oil Red O staining. The core molecular mechanism was studied through transcriptomics, and the expressions of the key pathway proteins were confirmed using Western blotting and immunohistochemistry. Results Treatment with JZHBD significantly reduced blood lipid and total bile acid levels, improved liver function and hepatic steatosis, and decreased aortic lipid deposition and plaque area in the mouse models of atherosclerosis. Transcriptomic analysis suggested that the therapeutic mechanism of JZHBD involved reverse cholesterol transport, PPAR signaling, and the inflammatory pathways. In atherosclerotic mice, JZHBD treatment obviously up-regulated hepatic expressions of PPARγ, LXRα, ABCA1, ABCG1, and CYP7A1, down-regulated hepatic expressions of p-p65/p65, IL-6, IL1β in the liver, increased ABCG5 and ABCG8 expressions in the intestines, and decreased ICAM-1 and VCAM-1 expressions in the aortic plaques. Conclusion JZHBD improves atherosclerotic vascular damage and plaque formation possibly by regulating hepatic reverse cholesterol transport and inflammation via modulating the hepatic PPARγ/LXRα/NF-κB signaling pathway.

Key words: atherosclerosis, qi meridian-blood channels, Jiangzhi Huaban Decoction, reverse cholesterol transport, vascular cell adhesion molecules

王宏杨, 朱文怡, 陈栩燊, 张童, 曹志伟, 王金, 解渤, 刘强, 任雪峰. “气经-血络”截断动脉粥样硬化斑块形成：降脂化斑方调控小鼠肝脏逆向胆固醇转运途径改善动脉粥样硬化的机制[J]. 南方医科大学学报, 2025, 45(9): 1818-1829.

Hongyang WANG, Wenyi ZHU, Xushen CHEN, Tong ZHANG, Zhiwei CAO, Jin WANG, Bo XIE, Qiang LIU, Xuefeng REN. Disrupting atherosclerotic plaque formation via the "qi meridian-blood channel": mechanism of Jiangzhi Huaban Decoction for regulating hepatic reverse cholesterol transport to improve atherosclerosis[J]. Journal of Southern Medical University, 2025, 45(9): 1818-1829.

图/表 7

图1 各组小鼠实验干预流程及同期体质量、肝质量的变化

Fig.1 Drug intervention flowchart (A) and changes in body (B) and liver weight (C) of the mice during treatment. *P<0.05, **P<0.01 vs NC group; #P<0.05, ##P<0.01 vs HFD group.

图3 小鼠主动脉转录组学差异表达基因的分析

Fig.3 Analysis of differentially expressed genes (DEGs) in mouse aortic transcriptomics. A: Volcano plot of DEGs in HFD group vs control and JZHB groups. B: Venn diagram of reversal genes in HFD group vs control and JZHB groups. C: Modular functional clustering analysis of reversal genes and the visualization of the "key gene-pathway" relationships using Sankey-Bubble plot diagrams.

图4 GO和KEGG功能富集分析

Fig.4 GO and KEGG functional enrichment analysis. A, B: GO functional enrichment analysis of JZHB against AS. C: KEGG pathway enrichment analysis of JZHB against AS. D: Schematic representation of the regulation of key targets of PPARγ/ LXRα/ NF-κB signaling pathway.

图5 各组小鼠肝脏、主动脉组织油红-O病理变化情况

Fig.5 Pathological changes in the liver and aortic tissue of the mice in each group. A: Oil Red O staining of the liver tissues in each group (Original magnification: ×200). B: Oil Red O staining of the aortic tissue in each group. **P<0.01 vs NC group; #P<0.05, ##P<0.01 vs HFD group.

图7 各组小鼠肝脏PPARγ/ LXRα/ NF-κB信号通路相关蛋白的变化

Fig.7 Changes of PPARγ/LXRα/NF-κB signaling pathway proteins in the liver of the mice in each group (Mean±SD, n=3). A: PPARγ, LXRα, ABCA1, ABCG1 and CYP7A1 protein expression in the livers of the mice. B: p65, p-p65, IL-6 and IL-1β protein expressions in the livers of the mice. **P<0.01 vs NC group; #P<0.05, ##P<0.01 vs HFD group.

图8 各组小鼠肠道ABCG5/G8相关蛋白的变化

Fig.8 Changes of ABCG5/G8-related proteins in the intestines of the mice in each group (n=3). **P<0.01 vs NC group, #P<0.05, ##P<0.01 vs HFD group.

图9 各组小鼠主动脉根斑块中ICAM-1、VCAM-1蛋白的变化

Fig.9 Immunohistochemistry for ICAM-1 (A) and VCAM-1 (B) proteins in aortic root plaques of the mice in each group (×100). **P<0.01 vs NC group, #P<0.05, ##P<0.01 vs HFD group.

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“气经-血络”截断动脉粥样硬化斑块形成：降脂化斑方调控小鼠肝脏逆向胆固醇转运途径改善动脉粥样硬化的机制

Disrupting atherosclerotic plaque formation via the "qi meridian-blood channel": mechanism of Jiangzhi Huaban Decoction for regulating hepatic reverse cholesterol transport to improve atherosclerosis

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