The effect and mechanism of <italic style="font-style: italic">Panax notoginseng</italic> saponins through inhibiting JNK/c-Jun signaling pathway in calcific aortic valve disease

LI Hongzheng; LIU Tianjiao; SHANG Zucheng; LI Mengfan; LIN Guosheng; ZHANG Bin; YU Zikai; FU Changgeng; WU Yongjian; CHEN Keji

doi:10.3969/j.issn.1006-2157.2024.11.010

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The effect and mechanism of Panax notoginseng saponins through inhibiting JNK/c-Jun signaling pathway in calcific aortic valve disease

Experimental Studies | 更新时间：2024-12-02

- The effect and mechanism of Panax notoginseng saponins through inhibiting JNK/c-Jun signaling pathway in calcific aortic valve disease
- Journal of Beijing University of Traditional Chinese Medicine Vol. 47, Issue 11, Pages: 1550-1561(2024)
- 作者机构：
  
  1.中国中医科学院西苑医院国家中医心血管病临床医学研究中心　北京　100091
  2.中国中医科学院广安门医院博士后流动站
  3.福建中医药大学中西医结合学院
  4.中国医学科学院阜外医院冠心病中心
- 作者简介：
  
  YU Zikai, Ph.D., Associate Researcher, Attending Physician. National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, No.1, Xiyuan Caochang Road, Haidian district, Beijing 100091. E-mail: ztyuzikai@163.com
- 基金信息：
  
  National Natural Science Foundation of China(82104679)
- DOI：10.3969/j.issn.1006-2157.2024.11.010
  CLC： R285.5
- Received：08 May 2024，
  
  Published：30 November 2024
- 稿件说明：
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LI Hongzheng, LIU Tianjiao, SHANG Zucheng, et al. The effect and mechanism of Panax notoginseng saponins through inhibiting JNK/c-Jun signaling pathway in calcific aortic valve disease[J]. Journal of Beijing University of Traditional Chinese Medicine, 2024, 47(11): 1550-1561. DOI: 10.3969/j.issn.1006-2157.2024.11.010.
DOI：

LI Hongzheng, LIU Tianjiao, SHANG Zucheng, et al. The effect and mechanism of Panax notoginseng saponins through inhibiting JNK/c-Jun signaling pathway in calcific aortic valve disease[J]. Journal of Beijing University of Traditional Chinese Medicine, 2024, 47(11): 1550-1561. DOI: 10.3969/j.issn.1006-2157.2024.11.010. DOI：

摘要

目的

探讨三七总皂苷调控c-Jun氨基端激酶(JNK)/c-Jun信号通路改善小鼠钙化性主动脉瓣疾病的作用与机制。

方法

将21只6～8周龄雄性ApoE

－/－

小鼠，按随机数字表法分

为模型组、三七总皂苷高剂量组(60 mg/kg)、三七总皂苷低剂量组(30 mg/kg)，每组7只；另设9只6～8周龄雄性C57BL/6小鼠为对照组。予对照组小鼠普通饲料饲养，予ApoE

－/－

小鼠高脂饲料饲养12周。12周后，随机选取ApoE

－/－

小鼠每组各1只和C57BL/6小鼠3只，评估造模效果。确认造模成功后，予三七总皂苷高、低剂量组小鼠每日灌胃相应药物，对照组、模型组小鼠灌胃等体积生理盐水，连续4周。治疗结束后，超声检测各组小鼠瓣环直径、峰值流速；硝酸银(von Kossa)染色、茜素红S染色评估主动脉瓣钙化程度；生化法检测甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)和高密度脂蛋白胆固醇(HDL-C)水平；酶联免疫吸附试验检测血清白细胞介素－4(IL-4) 、肿瘤坏死因子－α(TNF-α)、白细胞介素－1β(IL-1β)、白细胞介素－10(IL-10)含量；免疫组织化学法检测钙化标志物Runt相关转录因子2(RUNX2)、骨形态发生蛋白2(BMP2)阳性染色率；TUNEL染色评估主动脉瓣细胞凋亡情况；实时荧光PCR、免疫荧光检测JNK/c-Jun信号通路相关指标mRNA表达和平均荧光强度。

结果

与对照组比较，模型组小鼠血清TC、TG、LDL-C、TNF-α、IL-1β升高，IL-4、IL-10降低，瓣环直径减小，峰值流速升高，von Kossa、茜素红S染色阳性面积占比增多，主动脉瓣细胞凋亡率升高，BMP2、RUNX2阳性染色率增加，JNK与c-Jun mRNA表达水平、p-JNK/JNK、p-c-Jun/c-Jun均升高(均

0.05)。与模型组比较，三七总皂苷低剂量组小鼠血清TC、LDL-C、TNF-α降低，瓣环直径增大，峰值流速降低，茜素红S染色阳性面积减少，BMP2、RUNX2阳性染色率、JNK和c-Jun mRNA表达水平、p-JNK/JNK、p-c-Jun/c-Jun均降低(均

0.05)；三七总皂苷高剂量组血清HDL-C、IL-4、IL-10升高，TC、LDL-C、TNF-α、IL-1β降低，瓣环直径增大，峰值流速降低，von Kossa与茜素红S染色阳性面积占比减少、细胞凋亡染色率降低，BMP2与RUNX2阳性染色率降低，JNK、c-Jun mRNA表达水平及p-JNK/JNK、p-c-Jun/c-Jun均降低(均

0.05)。

结论

三七总皂苷可通过抑制JNK/c-Jun信号通路，减少瓣膜细胞凋亡，降低炎症水平，减轻小鼠主动脉瓣钙化程度。

Abstract

Objective

To investigate the effect and mechanism of

Panax notoginseng

saponins (PNS) in inhibiting c-Jun N-terminal protein kinase (JNK)/c-Jun signaling pathway activation to alleviate calcific aortic valve disease (CAVD) in mice.

Methods

Twenty-one male ApoE

-/-

mice aged 6 to 8 weeks were randomly divided into the model

PNS high-dose (60 mg/kg)

and PNS low-dose (30 mg/kg) groups using the random number table method

with seven mice per group. Nine male C57BL/6 mice aged 6 to 8 weeks were used as the control group. Mice in the control group were fed a normal diet

whereas ApoE

-/-

mice were fed a high-fat diet for 12 weeks. After 12 weeks

three C57BL/6 and

three ApoE

-/-

mice (one ApoE

-/-

mice from each group) were randomly selected to evaluate the CAVD modeling effect. After confirming successful modeling

the PNS high- and low-dose groups received daily intragastric PNS administration. The control and model groups were administered an equal volume of stroke-physiological saline solution by gavage for 4 consecutive weeks. The valve annulus diameter and peak velocity of the mice in each group were then detected using ultrasound. The degree of aortic valve calcification was evaluated using von Kossa and Alizarin Red S staining. The serum triglycerides (TG)

total cholesterol (TC)

low-density lipoprotein cholesterol (LDL-C)

and high-density lipoprotein cholesterol (HDL-C) were detected by biochemical method. Inflammatory factor interleukin-4 (IL-4)

tumor necrosis factor-α (TNF-α)

interleukin-1β (IL-1β)

and interleukin-10 (IL-10) levels were determined using an enzyme-linked immunosorbent assay. The expressions of calcification markers

runt-related transcription factor 2 (RUNX2)

and bone morphogenetic protein 2 (BMP2) were detected using immunohistochemistry. Aortic valve cell apoptosis was evaluated using TUNEL staining

and JNK/c-Jun signaling pathway-related mRNA and mean fluorescence intensity were detected using quantitative real-time PCR and immunofluorescence

respectively.

Results

Compared with the control group

the mice in the model group showed an increase in serum TC

LDL-C

TNF-α

and IL-1β levels

a decrease in IL-4 and IL-10 levels

a decrease in annulus diameter

an increase in peak flow velocity

and an increase in von Kossa and Alizarin Red S staining-positive areas. Additionally

the model group showed an increase in aortic valve cell apoptosis rate

an increase in BMP2 and RUNX2-positive rates

and an increase in JNK and c-Jun mRNA expression levels and p-JNK/JNK and p-c-Jun/c-Jun (

0.05). Compared to the model group

the PNS low-dose group showed a decrease in seru

m TC

LDL-C

and TNF-α levels

an increase in annulus diameter

a decrease in peak flow velocity

and a decrease in positive area in Alizarin Red S staining. Furthermore

the PNS low-dose group showed a decrease in BMP2 and RUNX2-positive rates

JNK and c-Jun mRNA expression levels

and p-JNK/JNK and p-c-Jun/c-Jun (

0.05). The PNS high-dose group showed an increase in HDL-C

IL-4 and IL-10 levels

a decrease in serum TC

LDL-C

TNF-α

and IL-1β levels

an increase in annulus diameter

a decrease in peak flow velocity

and a decrease in von Kossa and Alizarin Red S staining-positive areas and cell apoptosis rate. The PNS high-dose group also showed a decrease in BMP2 and RUNX2 positive staining rates

JNK and c-Jun mRNA expression levels

and p-JNK/JNK and p-c-Jun/c-Jun (

0.05).

Conclusion

PNS may reduce valvular cell apoptosis

alleviate inflammation

and protect against aortic valve calcification in mice by inhibiting the activation of JNK/c-Jun signaling pathway.

关键词

Keywords

references

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⁰

The effect and mechanism of Panax notoginseng saponins through inhibiting JNK/c-Jun signaling pathway in calcific aortic valve disease

DOI：10.3969/j.issn.1006-2157.2024.11.010

摘要

Abstract

关键词

Keywords

references