Mechanism of Zhishi Xiebai Guizhitang in Alleviating Myocardial Injury in Rats with Myocardial Infarction Based on TNF/NF-<italic style="font-style: italic">κ</italic>B Signaling Pathway

LIN Ziwei; WU Liujun; WU Huihui; XIE Xiaofang; PENG Cheng

doi:10.13422/j.cnki.syfjx.20230844

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Mechanism of Zhishi Xiebai Guizhitang in Alleviating Myocardial Injury in Rats with Myocardial Infarction Based on TNF/NF-κB Signaling Pathway

更新时间：2023-08-22

- Mechanism of Zhishi Xiebai Guizhitang in Alleviating Myocardial Injury in Rats with Myocardial Infarction Based on TNF/NF-κB Signaling Pathway
- Chinese Journal of Experimental Traditional Medical Formulae Vol. 29, Issue 18, Pages: 8-16(2023)
- 作者机构：
  
  1.成都中医药大学药学院，西南特色中药资源国家重点实验室，成都 611137
  2.成都华神科技集团股份有限公司，成都 610000
- 作者简介：
- 基金信息：
- DOI：10.13422/j.cnki.syfjx.20230844
  CLC： R2-0;R33;R714.252;R289
- Published：20 September 2023，
  
  Published Online：12 July 2023，
  
  Received：20 April 2023，
- 稿件说明：
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林紫薇,武柳君,吴晖晖等.基于TNF/NF-κB信号通路探讨枳实薤白桂枝汤减轻心肌梗死大鼠心肌损伤的作用机制[J].中国实验方剂学杂志,2023,29(18):8-16.

LIN Ziwei,WU Liujun,WU Huihui,et al.Mechanism of Zhishi Xiebai Guizhitang in Alleviating Myocardial Injury in Rats with Myocardial Infarction Based on TNF/NF-κB Signaling Pathway[J].Chinese Journal of Experimental Traditional Medical Formulae,2023,29(18):8-16.
林紫薇,武柳君,吴晖晖等.基于TNF/NF-κB信号通路探讨枳实薤白桂枝汤减轻心肌梗死大鼠心肌损伤的作用机制[J].中国实验方剂学杂志,2023,29(18):8-16. DOI： 10.13422/j.cnki.syfjx.20230844.

LIN Ziwei,WU Liujun,WU Huihui,et al.Mechanism of Zhishi Xiebai Guizhitang in Alleviating Myocardial Injury in Rats with Myocardial Infarction Based on TNF/NF-κB Signaling Pathway[J].Chinese Journal of Experimental Traditional Medical Formulae,2023,29(18):8-16. DOI： 10.13422/j.cnki.syfjx.20230844.

摘要

目的

从肿瘤坏死因子/核转录因子-

B（TNF/NF-

B）信号通路探讨枳实薤白桂枝汤（ZXGT）对异丙肾上腺素（ISO）诱导的大鼠心肌梗死（MI）的影响。

方法

将48只SD大鼠随机分为空白组、模型组、培哚普利组（4 mg·kg

-1

）、ZXGT组（24.4 g·kg

-1

）、ZXGT+抑制剂组（ZXGT，24.4 g·kg

-1

；TNF-

受体抑制剂R7050，5 mg·kg

-1

）、抑制剂组（R7050，5 mg·kg

-1

），每组8只；各组大鼠预防性灌胃给药7 d，且ZXGT+抑制剂组、抑制剂组在第6、第7天给予腹腔注射抑制剂R7050 5 mg·kg

-1

，除空白组外其余各组腹腔注射ISO，连续2 d，诱导大鼠MI模型；于实验第7天注射ISO 30 min后麻醉大鼠，检测心电图（ECG）观察ST段抬高值；采用小动物超声心动图检测大鼠心脏整体轴向应变（GLS）和心脏同步性；腹主动脉取血测定血清心肌肌钙蛋白T（cTnT）、肌酸激酶MB同工酶（CK-MB）、乳酸脱氢酶（LDH）水平及炎症因子TNF-

、白细胞介素-1

（IL-1

）水平；苏木素-伊红（HE）染色观察心肌组织病理变化；免疫组化（IHC）法检测心脏组织TNF-

、NF-

B p65、磷酸化（p）-NF-

B p65蛋白表达；蛋白免疫印迹法（Western blot）检测心脏组织肿瘤坏死因子受体1（TNFR1）、肿瘤坏死因子受体相关因子2（TRAF2）、转化生长因子激酶1（TAK1）、NF-

B抑制蛋白

（I

）、p-I

、NF-

B p65、p-NF-

B p65蛋白表达。

结果

与空白组比较，模型组大鼠ECG ST段显著抬高（

0.01），超声心动图中GLS增大及同步性显著降低（

0.01），病理组织学显示心肌大面积坏死，血清cTnT、CK-MB、LDH、TNF-

、IL-1

水平显著升高（

0.01），心肌组织中的TNF-

、TNFR1、TRAF2、TAK1、p-I

、p-NF-

B p65蛋白表达水平显著升高（

0.01），I

蛋白表达水平显著降低（

0.01）；与模型组比较，培哚普利组、ZXGT组、ZXGT+抑制剂组和抑制剂组大鼠的ECG ST段抬高值明显降低（

0.05，

0.01），GLS和心脏同步性改善（

0.05，

0.01），心肌坏死面积减小，血清cTnT、CK-MB、LDH、TNF-

、IL-1

水平均下调（

0.01），且ZXGT组、ZXGT+抑制剂组和抑制剂组均下调模型大鼠升高的TNF-

、TNFR1、TRAF2、TAK1、p-I

、p-NF-

B p65蛋白表达水平和上调I

的表达水平（

0.05，

0.01）；与ZXGT组比较，ZXGT+抑制剂组和抑制剂组差异无统计学意义。

结论

ZXGT能保护ISO诱导的大鼠MI损伤，改善心脏功能，其作用机制可能与调控TNF/NF-

B信号通路有关。

Abstract

Objective

To investigate the effect of Zhishi Xiebai Guizhitang （ZXGT） on isoproterenol （ISO）-induced myocardial infarction （MI） in rats through the tumor necrosis factor/nuclear factor-

B （TNF/NF-

B） signaling pathway.

Method

Forty-eight SD rats were randomly divided into control group （blank）， model group， perindopril group （4 mg·kg

-1

）， ZXGT group （24.4 g·kg

-1

）， ZXGT +inhibitor group （ZXGT， 24.4 g·kg

-1

， TNF-

receptor inhibitor R7050， 5 mg·kg

-1

）， and an inhibitor group （R7050， 5 mg·kg

-1

）， with eight rats in each group. The rats in each group were orally administered with their respective drugs for 7 days. Additionally， in the ZXGT + inhibitor group and the inhibitor group， R7050 was injected intraperitoneally at a dose of 5 mg·kg

-1

on the 6

and 7

days. Except for the control group， all other groups were given intraperitoneal injections of ISO for 2 consecutive days to induce MI in rats. On the 7

day of the experiment， the rats were anesthetized 30 min after ISO injection， and their electrocardiograms （ECGs） were recorded to observe ST-segment elevation. Small animal echocardiography was used to measure global longitudinal strain （GLS） and cardiac synchrony. Blood samples were collected from the abdominal aorta to measure the levels of serum cardiac troponin T （cTnT）， creatine kinase-MB （CK-MB）， lactate dehydrogenase （LDH）， tumor necrosis factor-

（TNF-

）， and interleukin-1

（IL-1

）. Histopathological changes in myocardial tissue were observed using hematoxylin-eosin （HE） staining. Immunohistochemistry （IHC） was used to detect the expression of TNF-

， NF-

B p65， and p-NF-

B p65 proteins in myocardial tissue. Western blot was performed to measure the expression of tumor necrosis factor receptor 1 （TNFR1）， tumor necrosis factor receptor-associated factor 2 （TRAF2）， transforming growth factor-beta-activated kinase 1 （TAK1）， NF-

B inhibitory protein alpha （I

）， phosphorylated （p）-I

， NF-

B p65， and p-NF-

B p65 proteins in myocardial tissue.

Result

Compared with the control group， the model group showed significant ST segment elevation on the ECG （

0.01）， increased GLS， and reduced cardiac synchrony on echocardiography （

0.01）. Histopathological examination revealed extensive myocardial necrosis. Furthermore， the serum levels of cTnT， CK-MB， LDH， TNF-

， and IL-1

were significantly increased （

0.01）， and the expression levels of TNF-

， TNFR1， TRAF2， TAK1， p-I

， and p-NF-

B p65 proteins in myocardial tissue were significantly elevated （

0.01）， while the expression level of I

was significantly decreased （

0.01）. Compared with the model group， the perindopril group， the ZXGT group， the ZXGT + inhibitor group， and the inhibitor group rats showed a significant reduction in ST-segment elevation on the ECG （

0.05，

0.01）， improvement in GLS and cardiac synchrony （

0.05，

0.01）， a decrease in the area of myocardial necrosis， and reduced serum levels of cTnT， CK-MB， LDH， TNF-

， and IL-1

（

0.01）. Additionally， the ZXGT group， the ZXGT + inhibitor group， and the inhibitor group downregulated the increased TNF-

， TNFR1， TRAF2， TAK1， p-I

， and p-NF-

B p65 protein expression levels and upregulated I

expression levels in the myocardial tissue （

0.05，

0.01）. No significant differences were observed between the ZXGT group and the ZXGT + inhibitor group or the inhibitor group.

Conclusion

ZXGT can protect against ISO-induced myocardial injury in rats and improve cardiac function， and its mechanism of action may be related to the regulation of the TNF/NF-

B signaling pathway.

关键词

枳实薤白桂枝汤心肌梗死肿瘤坏死因子/核转录因子-κB（TNF/NF-κB）通路炎症

Keywords

Zhishi Xiebai Guizhitangmyocardial infarctiontumor necrosis factor/nuclear factor-κB（TNF/NF-κB） pathwayinflammation

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Mechanism of Zhishi Xiebai Guizhitang in Alleviating Myocardial Injury in Rats with Myocardial Infarction Based on TNF/NF-κB Signaling Pathway

DOI：10.13422/j.cnki.syfjx.20230844

摘要

Abstract

关键词

Keywords

references