Sulodexide inhibits neointimal hyperplasia of arteriovenous fistulas in rats through inactivation of YAP

Yaxin LI; Bingyu LI; Xin LIN; Xuan LIU; Chenglin DAI; Yu ZHAO; Qining FU; Yun WANG

doi:10.16016/j.2097-0927.202309095

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Sulodexide inhibits neointimal hyperplasia of arteriovenous fistulas in rats through inactivation of YAP

Basic Medicine | 更新时间：2026-01-09

- Sulodexide inhibits neointimal hyperplasia of arteriovenous fistulas in rats through inactivation of YAP
- Journal of Army Medical University Vol. 46, Issue 12, Pages: 1403-1409(2024)
- 作者机构：
  
  1.400016 重庆，重庆医科大学附属第一医院血管外科
  2.400038 重庆，陆军军医大学(第三军医大学)基础医学院细胞生物学教研室
- 作者简介：
- 基金信息：
  
  the Talent Support Program of Army Medical University （Third Military Medical University）(2019);the Joint Medical Research Project of Chongqing Science and Technology Commission and Chongqing Health Commission(2021MSXM256)
- DOI：10.16016/j.2097-0927.202309095
  CLC： R364.31;R692;R973.2
- Received：18 September 2023，
  
  Revised：2023-10-25，
  
  Published：30 June 2024
- 稿件说明：
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Yaxin LI, Bingyu LI, Xin LIN, et al. Sulodexide inhibits neointimal hyperplasia of arteriovenous fistulas in rats through inactivation of YAP[J]. Journal of Army Medical University, 2024, 46(12): 1403-1409.
DOI：

Yaxin LI, Bingyu LI, Xin LIN, et al. Sulodexide inhibits neointimal hyperplasia of arteriovenous fistulas in rats through inactivation of YAP[J]. Journal of Army Medical University, 2024, 46(12): 1403-1409. DOI： 10.16016/j.2097-0927.202309095.

摘要

目的

研究舒洛地特(sulodexide

SDX)对慢性肾脏疾病(chronic kidney disease

CKD)大鼠动静脉瘘(arteriovenous fistula

AVF)新生内膜增生的作用及调节机制。

方法

选取体质量(300±50) g雄性大鼠18只

随机分为3组(

=6): AVF组

对正常大鼠进行AVF手术; 慢性肾病组(CKD+AVF)

大鼠经诱导慢性肾病后进行AVF手术+生理盐水灌胃2月; 舒洛地特组(CKD+AVF+SDX)

大鼠经诱导慢性肾病后进行AVF手术+8 mg/(kg·d) SDX灌胃2月。HE染色检测血管内膜增生程度

免疫荧光检测Hippo信号通路相关分子YAP、pYAP、YAP下游靶蛋白间充质细胞标志分子(connective tissue growth factor

CTGF)表达情况。以不同浓度SDX (0、2.5、5、10、20、40 μg/mL)处理人脐静脉细胞融合细胞(EAHy926)

并以2.5 μg/mL SDX分别处理细胞24、48、72 h

用CCK-8法检测细胞存活率。进一步利用CKD大鼠血清处理细胞

并在此基础上用SDX及YAP阻断剂维替泊芬处理

通过Western blot实验检测YAP、pYAP、CTGF及内皮细胞标志分子CD31表达。

结果

HE染色及免疫荧光结果表明

与AVF组大鼠相比

慢性肾病组大鼠瘘口处内膜严重增生(

0.05)

pYAP表达微弱而CTGF表达增强

舒洛地特组经SDX灌胃处理后内膜增生减轻

pYAP表达增强

CTGF表达水平降低(

0.05)。CCK-8结果表明

随SDX浓度及处理时间的增加

细胞存活率降低(

0.05)。Western blot结果发现

SDX促进EAHy926细胞pYAP及CD31的表达

抑制了CTGF的表达(

0.05)

与维替泊芬处理效果一致。

结论

舒洛地特通过阻止CKD引起的YAP激活

减轻了AVF血管内膜增生。

Abstract

Objective

To explore the role of sulodexide (SDX) in neointimal hyperplasia of arteriovenous fistulas (AVFs) in chronic kidney disease (CKD) rats and its possible mechanism.

Methods

A total of 18 male rats (weighing 300±50 g) were randomly and equally divided into AVF group

CKD+AVF group (CKD induction followed by AVF surgery and then gavaged with normal saline for 2 months)

and CKD+AVF+SDX group[treated as in the CKD+AVF group but with 8 mg/(kg·d) SDX gavage].HE staining was used to observe the degree of neointimal hyperplasia.The expression of Hippo pathway related molecules

Yes-associated protein (YAP)

pYAP and connective tissue growth factor (CTGF

YAP downstream target protein

one of mesenchymal marker) was detected by immunofluorescence assay.After human umbilical vein cell fusion EAHy926 cells were treated with 0

2.5

20 or 40 μg/mL SDX for 24 h

and with 2.5 μg/mL SDX for 24

48 or 72 h

respectively

CCK-8 assay was used to measure cell survival rate.Moreover

the serum sample from CKD rat was used to treat EAHy926 cells

and then the cells were treated with SDX or YAP inhibitor verteporfin.The expression levels of YAP

pYAP

CTGF and endothelial cell marker CD31 were detected by Western blotting.

Results

HE staining and immunofluorescence assay showed that CKD rats had serious neointimal hyperplasia in AVFs (

0.05)

and slightly lower expression of pYAP and enhanced expression of CTGF (

0.05) when compared with the rats of the AVF group.While

SDX treatment alleviated the neointimal hyperplasia of AVFs

enhanced the expression of pYAP and reduced the expression of CTGF (

0.05).CCK-8 assay showed that cell survival rate was decreased significantly in a dose-and time-dependent manner after SDX treatment (

0.05).Western blotting revealed that SDX increased the expression of pYAP and CD31 while inhibited the expression of CTGF in EAHy926 cells (

0.05)

which was consistent with the effect of verteporfin treatment.

Conclusion

SDX can block YAP activation caused by CKD and attenuate neointimal hyperplasia in AVFs.

关键词

Keywords

references

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