Treg Immunomodulation Contributes to the Anti-atherosclerotic Effects of Huxin Formula in ApoE<sup>-/-</sup> Mice

OU Xiao-min; CAI Jing; HU Xiao-yue; ZENG Qiao-huang; LAN Tao-hua; JIANG Wei

doi:10.1007/s11655-024-3663-2

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Treg Immunomodulation Contributes to the Anti-atherosclerotic Effects of Huxin Formula in ApoE^-/- Mice

Original Article | Updated：2024-09-23

- Treg Immunomodulation Contributes to the Anti-atherosclerotic Effects of Huxin Formula in ApoE^-/- Mice
- Chinese Journal of Integrative Medicine Vol. 30, Issue 10, Pages: 896-905(2024)
- Affiliations：
  
  1.The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou (510405), China
  2.Department of Cardiology, Guangdong Provincial Hospital of Chinese Medicine,the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou (510020), China
  3.Guangdong Provincial Key Laboratory of Chinese Medicine for Prevention and Treatment of Refractory Chronic Diseases, Guangzhou (510020), China
- Author bio：
  
  Dr. JIANG Wei, E-mail: jiangwei@gzucm.edu.cn
- Funds：
- DOI：10.1007/s11655-024-3663-2
  CLC：
- Published：2024-10，
  
  Published Online：16 May 2024，
  
  Accepted：21 February 2024
- Accepted：
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OU Xiao-min, CAI Jing, HU Xiao-yue, et al. Treg Immunomodulation Contributes to the Anti-atherosclerotic Effects of Huxin Formula in ApoE^-/- Mice. [J]. Chinese Journal of Integrative Medicine 30(10):896-905(2024)
DOI：

OU Xiao-min, CAI Jing, HU Xiao-yue, et al. Treg Immunomodulation Contributes to the Anti-atherosclerotic Effects of Huxin Formula in ApoE^-/- Mice. [J]. Chinese Journal of Integrative Medicine 30(10):896-905(2024) DOI： 10.1007/s11655-024-3663-2.

摘要

目的:

探讨护心方 (HXF) 对动脉粥样硬化的疗效及潜在机制.

方法:

根据随机数字法

在实验Ⅰ中将24只无特定病原体的雄性ApoE

-/-

小鼠随机分成模型组、HXF低剂量 (HXF-L) 组 (每天8.4g/kg) 、HXF高剂量 (HXF-H) 组 (每天16.8g/kg) 和普伐他汀组 (每天8mg/kg) (每组

=6) . C57BL/6J小鼠为对照组 (

=6) . HXF-L、HXF-H和普伐他汀组的ApoE

-/-

小鼠均给予西方饮食喂养

并连续灌胃给药12周. 对照组的C57BL/6J小鼠给予普通饲料喂养12周. 进一步在实验Ⅱ(每组

=6)中

通过每周腹腔注射纯化的抗小鼠CD25抗体(PC61

250μg/只)连续4周

耗竭小鼠体内Tregs. 采用油红O和Masson染色评估主动脉根斑块面积和纤维化程度. 流式检测淋巴结和脾脏中CD4+CD25+Foxp3+Treg数量. 采用MILLIPLEX

MAP技术检测血清转化生长因子-β1 (TGF-β1) 、白细胞介素 (IL) -10、IL-6水平. 采用实时定量反转录PCR (qRT-PCR) 和Western blot检测主动脉组织中TGF-β mRNA及蛋白的表达. 免疫荧光染色检测主动脉根部CD4+T淋巴细胞、巨噬细胞和平滑肌细胞的表达.

结果:

HXF能减少ApoE

-/-

小鼠斑块面积(

0.01)

增加小鼠淋巴结和脾脏中Treg计数 (

0.05或

0.01) . 另外

HXF通过提高ApoE

-/-

小鼠血清IL-10和TGF-β1水平 (

0.05)

降低血清IL-6水平 (

0.05) 来减轻炎症反应. HXF还上调了主动脉TGF-βmRNA及蛋白表达 (

0.05) . 同时

HXF均减少了主动脉根斑块中CD4+T淋巴细胞、巨噬细胞和平滑肌细胞的浸润 (

0.01) . 此外

CD25抗体 (PC61) 耗竭Tregs后抑制了HXF对斑块面积和主动脉根部纤维化的减少 (

0.01) .

结论:

HXF可能通过增加Treg来抑制炎症反应、减少炎症细胞浸润和减轻主动脉根部纤维化

从而减缓动脉粥样硬化.

Abstract

Objective:

To explore the effects of Huxin formula (HXF) in curtailing atherosclerosis and its underlying mechanism.

Methods:

According to random number table method

24 specific pathogen free male ApoE

-/-

mice were randomly divided into model group

HXF low-dose (HXF-L) group (8.4 g/kg daily)

HXF high-dose (HXF-H) group (16.8 g/kg daily)

and pravastatin (8 mg/kg daily) group in Experiment Ⅰ (

=6 per group). C57BL/6J mice served as the control group (

=6). ApoE

-/-

mice in HXF-L

HXF-H

pravastatin groups were fed a Western diet and administered continuously by gavage for 12 weeks

while C57BL/6J mice in the control group were fed conventional lab mouse chow for 12 weeks. Further

Tregs were depleted by weekly intraperitoneal

injection of purified anti-mouse CD25 antibody (PC61

250 μg per mouse) for 4 weeks in Experiment Ⅱ (

=6 per group). Oil Red O and Masson staining were used to evaluate the plaque area and aortic root fibrosis. The CD4

CD25

Foxp3

Treg counts in the lymph nodes and spleen cells were detected using flow cytometric analysis. The transforming growth factor-β1 (TGF-β1)

interleukin (IL)-10

and IL-6 serum levels were examined by MILLIPLEX

MAP technology. Quantitative real-time reverse transcription PCR (qRT-PCR) and Western blot were utilized to assess the expression of TGF-β mRNA and protein in the aorta. The expression of CD4

T lymphocytes

macrophages and smooth muscle cells in the aortic root were detected by immunofluorescence staining.

Results:

HXF reduced plaque area in ApoE

-/-

mice (

0.01). HXF increased the Treg counts in the lymph nodes and spleen cells (

0.05 or

0.01). Moreover

HXF alleviated inflammatory response via elevating IL-10 and TGF-β1 serum levels (

0.05)

while decreasing the IL-6 serum levels in ApoE

-/-

mice (

0.05). Also

HXF upregulated the expression of TGF-β mRNA and protein in the aorta (

0.05). Additionally

HXF attenuated CD4

T lymphocytes

macrophages and smooth muscle cells in aortic root plaque (

0.01). Furthermore

the depletion of Tregs with CD25 antibody (PC61) curtailed the reduction in plaque area and aortic root fibrosis by HXF (

0.01).

Conclusion:

HXF relieved atherosclerosis

probably by restraining inflammatory response

reducing inflammatory cell infiltration and attenuating aortic root fibrosis by increasing Treg counts.

关键词

动脉粥样硬化护心方Tregs免疫反应炎症

Keywords

atherosclerosisHuxin FormulaTregsimmune responsesinflammation

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Treg Immunomodulation Contributes to the Anti-atherosclerotic Effects of Huxin Formula in ApoE-/- Mice

DOI：10.1007/s11655-024-3663-2

摘要

Abstract

关键词

Keywords

references

Treg Immunomodulation Contributes to the Anti-atherosclerotic Effects of Huxin Formula in ApoE^-/- Mice