桂枝汤桂枝-白芍不同比例配伍通过调节TGF-<italic style="font-style: italic">β</italic><sub>1</sub>/Smads信号通路及慢性炎症改善盐敏感高血压大鼠心肌纤维化

陈纪烨; 周国锋; 王永成; 马度芳; 迟辰昱; 韩晓伟; 张永健; 李晓

doi:10.13422/j.cnki.syfjx.20200101

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桂枝汤桂枝-白芍不同比例配伍通过调节TGF-β₁/Smads信号通路及慢性炎症改善盐敏感高血压大鼠心肌纤维化

配伍 | 更新时间：2021-02-09

- 桂枝汤桂枝-白芍不同比例配伍通过调节TGF-β₁/Smads信号通路及慢性炎症改善盐敏感高血压大鼠心肌纤维化
- Effect of Guizhitang with Different Proportions of Cinnamomi Ramulus and Paeoniae Alba Radix in Regulating TGF-β₁/Smads Signaling Pathway and Chronic Inflammation and Alleviating Myocardial Fibrosis in Salt-sensitive Hypertensive Rats
- 中国实验方剂学杂志 2020年26卷第1期页码：50-58
- 作者机构：
  
  1.山东中医药大学，济南　 250014
  2.山东中医药大学　附属医院，济南　 250014
- 作者简介：
  
  [第一作者]　陈纪烨，在读硕士，从事心血管疾病的中西医结合诊疗、心肌微血管损伤与自主神经重构研究，E-mail: chenjy037@163.com
  *李晓，博士，主任医师，教授，从事心血管疾病的中西医结合诊疗、心肌微血管损伤与自主神经重构研究，Tel：0531-68616009，E-mail: lixiao617@163.com
- 基金信息：
  
  国家自然科学基金项目(81673970)
- DOI：10.13422/j.cnki.syfjx.20200101
  中图分类号： R2-0; R22; R285.5; R289
- 收稿日期：2019-06-04，
  
  网络出版日期：2019-09-11，
  
  纸质出版日期：2020-01-05
- 稿件说明：
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陈纪烨, 周国锋, 王永成, 等. 桂枝汤桂枝-白芍不同比例配伍通过调节TGF-β₁/Smads信号通路及慢性炎症改善盐敏感高血压大鼠心肌纤维化[J]. 中国实验方剂学杂志, 2020,26(1):50-58.

Ji-ye CHEN, Guo-feng ZHOU, Yong-cheng WANG, et al. Effect of Guizhitang with Different Proportions of Cinnamomi Ramulus and Paeoniae Alba Radix in Regulating TGF-β₁/Smads Signaling Pathway and Chronic Inflammation and Alleviating Myocardial Fibrosis in Salt-sensitive Hypertensive Rats[J]. Chinese journal of experimental traditional medical formulae, 2020, 26(1): 50-58.
陈纪烨, 周国锋, 王永成, 等. 桂枝汤桂枝-白芍不同比例配伍通过调节TGF-β₁/Smads信号通路及慢性炎症改善盐敏感高血压大鼠心肌纤维化[J]. 中国实验方剂学杂志, 2020,26(1):50-58. DOI： 10.13422/j.cnki.syfjx.20200101.

Ji-ye CHEN, Guo-feng ZHOU, Yong-cheng WANG, et al. Effect of Guizhitang with Different Proportions of Cinnamomi Ramulus and Paeoniae Alba Radix in Regulating TGF-β₁/Smads Signaling Pathway and Chronic Inflammation and Alleviating Myocardial Fibrosis in Salt-sensitive Hypertensive Rats[J]. Chinese journal of experimental traditional medical formulae, 2020, 26(1): 50-58. DOI： 10.13422/j.cnki.syfjx.20200101.

摘要

目的：

观察桂枝汤不同桂枝-白芍比例配伍对盐敏感高血压大鼠转化生长因子-

(TGF-

)/Smads信号通路以及白细胞介素-10(IL-10)，IL-6，肿瘤坏死因子-

(TNF-

)相关炎症因子表达的影响，探讨桂枝汤改善盐敏感高血压大鼠心肌纤维化具体的机制。

方法：

将40只雄性6周龄盐敏感大鼠随机分为5组，分别为正常组、模型组、桂枝汤桂枝-白芍1∶1组(简称桂芍1∶1组)、桂枝汤桂枝-白芍1∶2组(简称桂芍1∶2组)、桂枝汤桂枝-白芍2∶1组(简称桂芍2∶1组)，每组8只。正常组给予低盐饲料喂养，其余4组给予高盐饲料喂养，喂养4周后开始灌胃，正常组、模型组每天给予等体积的生理盐水灌胃，桂芍1∶1组、桂芍1∶2组和桂芍2∶1组分别按4.0，5.5，5.5 g·kg

-1

给予桂枝汤水溶液灌胃，连续灌胃4周。每周测量1次血压；采用超声心动图检测左室收缩末期内径(LVESD)，左室舒张末期内径(LVEDD)，左室射血分数(LVEF)，左室短轴缩短分数(LVFS)；采用苏木素-伊红(HE)及马松(Masson)染色观察各组大鼠心肌病理形态变化；采用免疫组化检测各组大鼠心肌组织中Ⅰ，Ⅲ型胶原蛋白的表达；采用实时荧光定量聚合酶链式反应(Real-time PCR)检测各组大鼠心肌组织中IL-10，IL-6，TNF-

mRNA的表达；采用蛋白免疫印迹法(Western blot)检测各组大鼠心肌组织中TGF-

，

-平滑肌肌动蛋白(

-SMA)，Smad2，Smad3，Smad7蛋白的表达。

结果：

与正常组比较，模型组在8～15周的血压升高，LVESD，LVEDD升高，LVFS，LVEF降低，胶原容积分数升高，免疫组化显示Ⅰ，Ⅲ型胶原蛋白的表达增加，IL-10，IL-6，TNF-

mRNA的表达均升高，TGF-

，Smad2，Smad3，

-SMA蛋白的表达升高，Smad7蛋白的表达降低(

0.01)。与模型组比较，桂枝汤各组在12～15周血压上升延缓，LVESD，LVEDD降低(

0.01)，LVFS，LVEF升高(

0.01)，胶原容积分数降低(

0.01)，Ⅰ，Ⅲ型胶原蛋白的表达降低(

0.01)，同时，IL-10 mRNA的表达升高(

0.05，

0.01)，IL-6，TNF-

mRNA的表达降低(

0.01)，TGF-

，Smad2，Smad3，

-SMA蛋白的表达降低(

0.05，

0.01)，Smad7蛋白的表达升高(

0.01)；且与桂芍2∶1组相比，桂芍1∶1组改善上述指标的效果更明显(

0.01)。

结论：

桂枝汤不同桂芍比例配伍可以改善盐敏感高血压大鼠的心肌纤维化程度，其机制可能与调节TGF-

/Smads信号通路及减轻炎症反应有关，且桂枝汤桂芍1∶1组减轻炎症反应，改善心肌纤维化效果最好。

Abstract

Objective:

To observe the effect of Guizhitang with different proportions of Cinnamomi Ramulus and Paeoniae Alba Radix on the expressions of transforming growth factor-

(TGF-

)/Smads signaling pathway and interleukin-10(IL-10)

IL-6 and tumour necrosis factor-

(TNF-

)related inflammatory cytokines in salt-sensitive hypertensive rats

in order to explore the mechanism of Guizhitang in improving myocardial fibrosis in salt-sensitive hypertensive rats.

Method:

Totally 40 male 6-week-old salt-sensitive rats were randomly divided into 5 groups: the normal control group

the model group

the 1∶1(RC/peony)Guishao group

the 1∶2 Guishao group

and the 2∶1 Guishao group

with 8 in each group. The normal control group was fed with normal salt diet

while the other four groups were fed with high-salt diet. After 4 weeks of feeding

the rats were given intragastric administration

the normal control group and the model group were given the same amount of normal saline

and the 1∶1 Guishao group

the 1∶2 Guishao group and the 2∶1 Guishao group were given 4.0

5.5

5.5 g·kg

-1

of Guizhitang by gavage for 4 weeks. Blood pressure was measured once a week

left ventricular end systolic diameter(LVESD)

left ventricular end diastolic diameter (LVEDD)

left ventricular ejection fraction (LVEF) and left ventricular short axis shortening fraction (LVFS) were detected by using echocardiogram. The pathological changes of myocardial morphology were observed by htoxylin eosin(HE)and Masson staining. The expressions of type Ⅰ and Ⅲ collagen in myocardial tissue of each group was detected by immunohistochemistry. The mRNA expression levels of IL-10

IL-6 and TNF-

in myocardial tissue of each group were detected by quantitative real-time fluorescence polymerase chain reaction(Real-time PCR). The protein expression levels of TGF-

-smooth muscle actin(

-SMA)

Smad2

Smad3 and Smad7 in myocardial tissue of each group were detected by Western blot.

Result:

Compared with the normal control group

the blood pressure was increased in the model group at 8-15 weeks

LVESD

LVEDD were increased in the model group

while LVFS

LVEF were decreased in the model group. The collagen volume fraction was increased

immunohistochemistry showed the expression levels of type Ⅰ and Ⅲ collagen were increased

mRNA expression levels of IL-10

IL-6 and TNF-

were increased

the protein expression levels of TGF-

Smad2

Smad3 and

-SMA were increased

whereas the protein expression of Smad7 was decreased (

0.01). Compared with the model group

the blood pressure rise of each group of Guizhitang was delayed in 12-15 weeks

LVESD and LVEDD were decreased in Guizhitang group (

0.01)

LVFS

LVEF were increased in Guizhitang group (

0.01)

the collagen volume fraction was decreased in Guizhitang group (

0.01)

and the expressions of type Ⅰ and Ⅲ collagen were decreased in Guizhitang group (

0.01). At the same time

the mRNA expression of IL-10 was increased in Guizhitang group (

0.05

0.01)

the mRNA expressions of IL-6 and TNF-

were decreased in Guizhitang group (

0.01)

and the protein expressions of TGF-

Smad2

Smad3 and

-SMA were decreased in Guizhitang group (

0.05

0.01)

and the protein expression of Smad7 was increased in Guizhitang group (

0.01). Compared with the 2∶1 Guishao group

the effect of the 1∶1 Guishao group in improving the above indicators was more obvious (

0.05

0.01).

Conclusion:

Guizhitang with different proportions of Ramulus Cinnamomi and Poeny can alleviate the degree of myocardial fibrosis in salt-sensitive hypertensive rats. The mechanism may be related to the regulation of TGF-

/Smads signaling pathway and the reduction of inflammatory response. Besides

the 1∶1 Guishao group showed the optimal effect in reducing inflammation and improving myocardial fibrosis.

关键词

Keywords

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Effect of Guizhitang with Different Proportions of Cinnamomi Ramulus and Paeoniae Alba Radix in Regulating TGF-β1/Smads Signaling Pathway and Chronic Inflammation and Alleviating Myocardial Fibrosis in Salt-sensitive Hypertensive Rats

DOI：10.13422/j.cnki.syfjx.20200101

摘要

Abstract

关键词

Keywords

references

桂枝汤桂枝-白芍不同比例配伍通过调节TGF-β₁/Smads信号通路及慢性炎症改善盐敏感高血压大鼠心肌纤维化

Effect of Guizhitang with Different Proportions of Cinnamomi Ramulus and Paeoniae Alba Radix in Regulating TGF-β₁/Smads Signaling Pathway and Chronic Inflammation and Alleviating Myocardial Fibrosis in Salt-sensitive Hypertensive Rats