基于HIF-1α-Angptl4 mRNA信号通路探讨丹蒌片抗低氧诱导血脂异常和动脉硬化的机制

Jing-jing TANG; Guang-xi LI; Zhi-guo LIU; Rong YI; Dong YU; Yue-bo ZHANG; Shuang-qiao ZHAO; Shi-han WANG

doi:10.1007/s11655-020-3255-8

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基于HIF-1α-Angptl4 mRNA信号通路探讨丹蒌片抗低氧诱导血脂异常和动脉硬化的机制

Original Article | Updated：2022-06-27

- 基于HIF-1α-Angptl4 mRNA信号通路探讨丹蒌片抗低氧诱导血脂异常和动脉硬化的机制
- Danlou Tablet Improves Chronic Intermittent Hypoxia-Induced Dyslipidemia and Arteriosclerosis by HIF-1α-Angptl4 mRNA Signaling Pathway
- Chinese Journal of Integrative Medicine 2022年28卷第6期页码：509-517
- Affiliations：
  
  1.Department of Pneumology, Guang'anmen Hospital, Chinese Academy of Chinese Medical Sciences, Beijing (100053), China
  2.Department of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN 55905, United States
  3.Drug Clinical Trial Agency, Guang'anmen Hospital, Chinese Academy of Chinese Medical Sciences, Beijing (100053), China
  4.Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN 55905, United States
  5.Department of Gynecology, Guang'anmen Hospital, Chinese Academy of Chinese Medical Sciences,Beijing (100053), China
  6.Department of Cardiovascular Medicine, Guang'anmen Hospital, Chinese Academy of Chinese Medical Sciences, Beijing (100053), China
- Author bio：
  
  Dr. WANG Shi-han, E-mail: wang.shihan@mayo.edu
- Funds：
  
  National Natural Science Foundation of China(81473465)
- DOI：10.1007/s11655-020-3255-8
  中图分类号：
- 纸质出版日期：2022-06-01，
  
  网络出版日期：2020-07-04，
  
  录用日期：2019-10-22
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Jing-jing TANG, Guang-xi LI, Zhi-guo LIU, 等. 基于HIF-1α-Angptl4 mRNA信号通路探讨丹蒌片抗低氧诱导血脂异常和动脉硬化的机制[J]. Chinese Journal of Integrative Medicine, 2022,28(6):509-517.

Jing-jing TANG, Guang-xi LI, Zhi-guo LIU, et al. Danlou Tablet Improves Chronic Intermittent Hypoxia-Induced Dyslipidemia and Arteriosclerosis by HIF-1α-Angptl4 mRNA Signaling Pathway[J]. Chinese Journal of Integrative Medicine, 2022,28(6):509-517.
Jing-jing TANG, Guang-xi LI, Zhi-guo LIU, 等. 基于HIF-1α-Angptl4 mRNA信号通路探讨丹蒌片抗低氧诱导血脂异常和动脉硬化的机制[J]. Chinese Journal of Integrative Medicine, 2022,28(6):509-517. DOI： 10.1007/s11655-020-3255-8.

Jing-jing TANG, Guang-xi LI, Zhi-guo LIU, et al. Danlou Tablet Improves Chronic Intermittent Hypoxia-Induced Dyslipidemia and Arteriosclerosis by HIF-1α-Angptl4 mRNA Signaling Pathway[J]. Chinese Journal of Integrative Medicine, 2022,28(6):509-517. DOI： 10.1007/s11655-020-3255-8.

摘要

目的:

研究丹蒌片 (DLT) 对低氧诱导因子(HIF) 1α-血管生成素样4 (Angptl4) mRNA信号通路的调节作用

探讨其抗慢性间歇性低氧(CIH)诱导的血脂异常与动脉硬化的作用机制.

方法:

通过3T3-L1细胞培养成熟脂肪细胞

并将其分为8组

包括对照组(1组和5组

细胞培养级超纯水0.1 mL)、DLT组(2组和6组

1000 μg/mL DLT亚微细米级粉剂溶液 0.1 mL)、二甲基草酰甘氨酸 (DMOG) 组( 3组和7组

DMOG和细胞培养级超纯水0.1 mL)、DMOG + DLT组(4组和8组

DMOG和1000 μg/mL DLT亚微细米级粉剂溶液0.1 mL). 1-4组采用成熟脂肪细胞

5-8组采用HIF-1α-siRNA慢病毒转染的成熟脂肪细胞. 处理24小时后

采用实时聚合酶链反应(RT-PCR)和蛋白质印迹 (Western blot) 法分别检测HIF-1α和Angptl4 mRNA及其蛋白表达水平. 在动物实验中

采用ApoE

-/-

小鼠建立CIH模型. 16只小鼠完全随机分为4组

包括假手术组、CIH模型组[间歇性低氧

生理盐水每日灌胃1次(2 mL/次)]、Angptl4抗体组[间歇性低氧

Angptl4抗体每周腹腔注射1次(30 mg/kg)]

及DLT组[间歇性低氧

DLT每日灌胃一次 (250 mg/kg)]

每组4只. 处理4周后

采用酶联免疫吸附(ELISA)法检测血清总胆固醇(TC)及甘油三酯(TG)表达. 采用苏木精-伊红染色(HE)和CD68染色法观察动脉斑块的形态学特征.

结果:

Angptl4的表达与HIF-1α相关

在HIF-1α-siRNA慢病毒转染的成熟脂肪细胞中

Angptl4 mRNA水平下降

但蛋白表达不受DMOG及DLT影响. 成熟脂肪细胞中

在DMOG低氧诱导情况下

DLT可抑制HIF-1α及Angptl4 mRNA水平(

0.05或

0.01)

降低HIF-1及Angptl4蛋白的表达(均

0.01)

该作用在siHIF-1慢病毒转染的情况下也存在(

0.01). CIH处理后

ApoE

-/-

小鼠TG及TC水平升高 (均

0.01)

动脉粥样硬化斑块加重. Angptl4抗体及DLT均可降低TG和TC水平 (均

0.01)

在一定程度上降低动脉粥样硬化斑块面积

缩小动脉壁厚度

减轻动脉粥样硬化病变症状.

结论:

DLT可通过HIF-1α-Angptl4 mRNA信号通路抑制Angptl4蛋白水平

从而改善血脂异常和动脉硬化.

Abstract

Objective:

To detect whether Danlou Tablet (DLT) regulates the hypoxia-induced factor (HIF)-1α- angiopoietin-like 4 (Angptl4) mRNA signaling pathway and explore the role of DLT in treating chronic intermittent hypoxia (CIH)-induced dyslipidemia and arteriosclerosis.

Methods:

The mature adipocytes were obtained from 3T3-L1 cell culturation and allocated into 8 groups including control groups (Groups 1 and 5

0.1 mL of cell culture grade water); DLT groups (Groups 2 and 6

0.1 mL of 1

000 μg/mL DLT submicron powder solution); dimethyloxalylglycine (DMOG) groups (Groups 3 and 7

DMOG and 0.1 mL of cell culture grade water); DMOG plus DLT groups (Groups 4 and 8

DMOG and 0.1 mL of 1

000 μg/mL DLT submicron powder solution). Groups 1–4 used mature adipocytes and groups 5–8 used HIF-1α-siRNA lentivirus-transfected mature adipocytes. After 24-h treatment

real-time polymerase chain reaction and Western blot were employed to determine the mRNA and protein expression levels of HIF-1α and Angptl4. In animal experiments

the CIH model in ApoE

-/-

mice was established. Sixteen mice were complete randomly divided into 4 groups including sham group

CIH model group [intermittent hypoxia and normal saline (2 mL/time) gavage once a day]

Angptl4 Ab group [intermittent hypoxia and Angptl4 antibody (30 mg/kg) intraperitoneally injected every week]

DLT group [intermittent hypoxia and DLT (250 mg/kg) once a day]

4 mice in each group. After 4-week treatment

enzyme linked immunosorbent assay was used to detect the levels of serum total cholesterol (TC) and triglyceride (TG). Hematoxylin-eosin and CD68 staining were used to observe the morphological properties of arterial plaques.

Results:

Angptl4 expression was dependent on HIF-1α

with a reduction in mRNA expression and no response in protein level to DMOG or DLT treatment in relation to siHIF-1α-transfected cells. DLT inhibited HIF-1α and Angptl4 mRNA expression (

0.05 or

0.01) and reduced HIF-1α and Angptl4 protein expressions with DMOG in mature adipocytes (all

0.01)

as the effect on HIF-1α protein also existed in the presence of siHIF-1α (

0.01). ApoE

-/-

mice treated with CIH had increased TG and TC levels (all

0.01) and atherosclerotic plaque. Angptl4 antibody and DLT both reduced TG and TC levels (all

0.01)

as well as reducing atherosclerotic plaque areas

narrowing arterial wall thickness and alleviating atherosclerotic lesion symptoms to some extent.

Conclusion:

DLT had positive effects in improving dyslipidemia and arteriosclerosis by inhibiting Angptl4 protein level through HIF-1α-Angptl4 mRNA signaling pathway.

关键词

Keywords

Danlou TabletChinese medicinehypoxia-induced factorangiopoietin-like 4dyslipidemiaarteriosclerosis

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