Effects of <italic style="font-style: italic">Liqi Huoxue Dripping Pill （</italic>理气活血滴丸<italic style="font-style: italic">）</italic> on Integrin-YAP/TAZ Pathway in Aorta of ApoE<sup>-/-</sup> Mice Model of Atherosclerosis

Tao XU; Yuhua ZHENG; Yu LEI; Li PENG; Qianqian HUANG; Ren GONG; Tingchun WU; Dawei LYU; Ting DENG; Chunyu MU

doi:10.13288/j.11-2166/r.2022.07.012

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Effects of Liqi Huoxue Dripping Pill （理气活血滴丸） on Integrin-YAP/TAZ Pathway in Aorta of ApoE^-/- Mice Model of Atherosclerosis

更新时间：2022-03-29

- Effects of Liqi Huoxue Dripping Pill （理气活血滴丸） on Integrin-YAP/TAZ Pathway in Aorta of ApoE^-/- Mice Model of Atherosclerosis
- Journal of Traditional Chinese Medicine Vol. 63, Issue 7, Pages: 671-678(2022)
- 作者机构：
  
  1.贵州中医药大学第二附属医院，贵州省贵阳市云岩区飞山街83号，550003
  2.贵州省血液中心
- 作者简介：
- 基金信息：
- DOI：10.13288/j.11-2166/r.2022.07.012
  CLC：
- Received：31 July 2021，
  
  Revised：2022-01-29，
  
  Published：02 April 2022
- 稿件说明：
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许滔,郑玉华,雷雨等.理气活血滴丸对动脉粥样硬化模型ApoE^-/-小鼠主动脉Integrin-YAP/TAZ通路的影响[J].中医杂志,2022,63(07):671-678. DOI: 10.13288/j.11-2166/r.2022.07.012.

XU Tao,ZHENG Yuhua,LEI Yu,et al.Effects of Liqi Huoxue Dripping Pill （理气活血滴丸） on Integrin-YAP/TAZ Pathway in Aorta of ApoE^-/- Mice Model of Atherosclerosis[J].Journal of Traditional Chinese Medicine,2022,63(07):671-678. DOI: 10.13288/j.11-2166/r.2022.07.012.
许滔,郑玉华,雷雨等.理气活血滴丸对动脉粥样硬化模型ApoE^-/-小鼠主动脉Integrin-YAP/TAZ通路的影响[J].中医杂志,2022,63(07):671-678. DOI: 10.13288/j.11-2166/r.2022.07.012. DOI：

XU Tao,ZHENG Yuhua,LEI Yu,et al.Effects of Liqi Huoxue Dripping Pill （理气活血滴丸） on Integrin-YAP/TAZ Pathway in Aorta of ApoE^-/- Mice Model of Atherosclerosis[J].Journal of Traditional Chinese Medicine,2022,63(07):671-678. DOI: 10.13288/j.11-2166/r.2022.07.012. DOI：

摘要

目的

探讨理气活血滴丸治疗动脉粥样硬化的可能作用机制。

方法

50只载脂蛋白基因E敲除（ApoE

-/-

）小鼠给予高脂饲料喂养制备动脉粥样硬化模型，将45只造模成功小鼠随机分为模型组、阿托伐他汀组及理气活血滴丸低、中、高剂量组，每组9只；9只C57BL/6J小鼠设为正常组。理气活血滴丸低、中、高剂量组分别给予理气活血滴丸75、150、300 mg/（kg·d）灌胃，阿托伐他汀组给予阿托伐他汀钙片2 mg/（kg·d）灌胃，正常组与模型组每日给予0.3 ml的蒸馏水灌胃。4周后采用油红O染色和HE染色观察各组小鼠主动脉弓根部病理变化，计算管腔内斑块面积占比，采用Western blot法测定主动脉中整合素αVβ3（IntegrinαVβ3）、Yes相关蛋白（YAP）、含PDZ结合序列的转录活化共因子（TAZ）、磷酸化Yes相关蛋白（p-YAP）、血管生成诱导剂61（CYR61）、结缔组织生长因子（CTGF）蛋白表达。

结果

与正常组比较，模型组小鼠主动脉壁可见明显动脉粥样硬化斑块，可见大量的脂质、柳叶状胆固醇结晶，动脉粥样硬化斑块面积占比及主动脉中IntegrinαVβ3、YAP、TAZ、CYR61、CTGF蛋白表达增多，p-YAP蛋白表达减少（

＜0.05或

＜0.01）；与模型组比较，理气活血滴丸各剂量组和阿托伐他汀组小鼠动脉粥样硬化斑块厚度降低，斑块内柳叶状胆固醇结晶和脂肪空泡减少，动脉粥样硬化斑块面积占比不同程度降低，YAP、TAZ蛋白表达减少，p-YAP蛋白表达增多，理气活血滴丸中剂量组、阿托伐他汀组IntegrinαVβ3蛋白表达减少，理气活血滴丸中、高剂量组及阿托伐他汀组CYR61、CTGF蛋白表达减少（

＜0.05或

＜0.01）；与阿托伐他汀组比较，理气活血滴丸各剂量组的斑块面积占比均升高，斑块内脂肪空泡和胆固醇结晶均增多，理气活血滴丸低、高剂量组p-YAP蛋白表达减少，理气活血滴丸低、中剂量组CYR61、CTGF蛋白表达增多，理气活血滴丸低剂量组IntegrinαVβ3蛋白表达增多（

＜0.05或

＜0.01）；与理气活血滴丸高剂量组比较，理气活血滴丸中剂量组斑块内脂肪空泡和胆固醇结晶均减少，结构相对致密，理气活血滴丸低、中剂量组CYR61、CTGF蛋白表达增多（

＜0.05或

＜0.01）；与理气活血滴丸中剂量组比较，理气活血滴丸低剂量组斑块内脂肪空泡和胆固醇结晶均增多，IntegrinαVβ3蛋白表达增多，p-YAP蛋白表达减少（

＜0.05或

＜0.01）。

结论

理气活血滴丸具有抗动脉粥样硬化的作用，其作用机制可能与调控主动脉Integrin-YAP/TAZ通路有关，以高剂量调控效果最佳。

Abstract

Objective

To explore the possible mechanism of

Liqi Huoxue Dripping Pill

（理气活血滴丸， LHDP） in treatment of atherosclerosis.

Methods

Fifty apolipoprotein gene E knockout （ApoE

-/-

） mice were fed with high fat diet to prepare the atherosclerosis model. Forty-five successfully modeled mice were randomly divided into model group， atorvastatin group， LHDP low-， medium- and high-dose groups， with 9 mice in each group. Nine C57BL/6J mice were set as normal group. LHDP low-， medium- and high-dose groups were given 75， 150 and 300 mg/（kg·d） of LHDP by gavage， respectively； atorvastatin group was given 2 mg/（kg·d） of atorvastatin calcium tablet by gavage，while the normal group and model group were administered with 0.3 ml distilled water daily by gavage. After four weeks， oil red O staining and HE staining were used to observe the pathological changes of aortic root in each group， and the proportion of lumen plaque area was calculated. Western blotting was used to determine the protein expression of integrin αVβ3 （IntegrinαVβ3）， YES-related protein （YAP）， PDZ binding sequence-containing transcription activation cofactor， phosphorylated YES-related protein （p-YAP）， angiogenesis inducer 61 （CYR61） and connective tissue growth factor （CTGF） in aorta.

Results

Compared to the normal group， there were obvious atherosclerotic plaque seen in the aorta wall in the model group， and a large number of lipid and willow leaf cholesterol crystals； the proportion of atherosclerotic plaque area and the expression of IntegrinαVβ3， YAP， TAZ， CYR61 and CTGF in aorta significantly increased， while the expression of p-YAP protein decreased （

＜0.05 or

＜0.01）. Compared to the model group， the thickness of atherosclerotic plaque， the willow-shaped cholesterol crystals and fat vacuoles in plaques， as well as the percentage of atherosclerotic plaque area were reduced with varying degrees； the expression of YAP and TAZ proteins decreased， while the expression of p-YAP protein increased in all three LHDP groups and atorvastatin group； the expression of IntegrinαVβ3 protein was reduced in LHDP medium-dose group and atorvastatin group； CYR61 and CTGF protein expression decreased in LHDP medium- and high-dose groups and atorvastatin group （

＜0.05 or

＜0.01）. Compared to atorvastatin group， the proportion of plaque area， and the fat vacuoles and cholesterol crystals increased in all three LHDP groups； p-YAP protein expression decreased in LHDP low- and high-dose groups； CYR61 and CTGF protein expression increased in LHDP low- and medium-dose groups； the expression of IntegrinαVβ3 protein increased in LHDP low-dose group （

＜0.05 or

＜0.01）. Compared to LHDP high-dose group， the fat vacuoles and cholesterol crystals in plaques were reduced， and the structure was relatively dense in LHDP medium-dose group； the expression of CYR61 and CTGF protein significantly increased in LHDP low- and medium-dose groups （

＜0.05 or

＜0.01）. Compared to LHDP medium-dose group， the fat vacuoles and cholesterol crystals in plaques increased in xxx group； the IntegrinαVβ3 protein expression increased， while the p-YAP protein expression decreased in the LHDP low-dose group （

＜0.05 or

＜0.01）.

Conclusion

LHDP has anti-atherosclerosis effect， which may be related to the regulation of the integrin-YAP /TAZ pathway of the aorta. The effect is best at high dose of LHDP.

关键词

Keywords

references

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⁰

Effects of Liqi Huoxue Dripping Pill （理气活血滴丸） on Integrin-YAP/TAZ Pathway in Aorta of ApoE-/- Mice Model of Atherosclerosis

DOI：10.13288/j.11-2166/r.2022.07.012

摘要

Abstract

关键词

Keywords

references

Effects of Liqi Huoxue Dripping Pill （理气活血滴丸） on Integrin-YAP/TAZ Pathway in Aorta of ApoE^-/- Mice Model of Atherosclerosis