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Endoplasmic Reticulum Stress-induced Endothelial Dysfunction Promotes Neointima Formation after Arteriovenous Grafts in Mice on High-fat Diet

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Abstract

Objective

Endothelial dysfunction is one candidate for triggering neointima formation after arteriovenous grafts (AVGs), but the factors mediating this process are unclear. The purpose of this study was to investigate the role of endoplasmic reticulum stress (ERS)-induced endothelial dysfunction in neointima formation following AVGs in high-fat diet (HFD) mice.

Methods

CCAAT-enhancer-binding protein-homologous protein (CHOP) knockout (KO) mice were created. Mice were fed with HFD to produce HFD model. AVGs model were applied in the groups of WT ND, WT HFD, and CHOP KO HFD. Human umbilical vein endothelial cells (HUVECs) were cultured with oxidized low density lipoprotein (ox-LDL) (40 mg/L) for the indicated time lengths (0, 6, 12, 24 h). ERS inhibitor tauroursodeoxycholic acid (TUDCA) was used to block ERS. Immunohistochemical staining was used to observe the changes of ICAM1. Changes of ERS were detected by real-time RT-PCR. Protein expression levels and ERS activation were detected by Western blotting. Endothellial cell function was determined by endothelial permeability assay and transendothelial migration assay.

Results

HFD increased neointima formation in AVGs associated with endothelial dysfunction. At the same time, ERS was increased in endothelial cells (ECs) after AVGs in mice consuming the HFD. In vitro, ox-LDL was found to stimulate ERS, increase the permeability of the EC monolayer, and cause endothelial dysfunction. Blocking ERS with TUDCA or CHOP siRNA reversed the EC dysfunction caused by ox-LDL. In vivo, knockout of CHOP (CHOP KO) protected the function of ECs and decreased neointima formation after AVGs in HFD mice.

Conclusion

Inhibiting ERS in ECs could improve the function of AVGs.

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Authors and Affiliations

  1. Emergency and Intensive Care Unit, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Yan-xia Zhong, Chen-chen Zhou, Ying-fang Zheng, Hong-kai Dai, Ren-yu Chen, Yu-rou Wang, Cheng-ye Zhan & Jin-long Luo

  2. Divison of Cardiothoracic and Vascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Ai-ni Xie

Authors
  1. Yan-xia Zhong
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  2. Chen-chen Zhou
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  3. Ying-fang Zheng
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  4. Hong-kai Dai
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Correspondence to Ai-ni Xie.

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The authors declare that they have no competing financial interests or personal relationships that influenced the work reported in this paper.

Additional information

This research was funded by the National Natural Science Foundation of China (No. 81770413) and Hubei Provincial Natural Science Foundation of China (No. 2017CFB669).

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Zhong, Yx., Zhou, Cc., Zheng, Yf. et al. Endoplasmic Reticulum Stress-induced Endothelial Dysfunction Promotes Neointima Formation after Arteriovenous Grafts in Mice on High-fat Diet. CURR MED SCI 43, 115–122 (2023). https://doi.org/10.1007/s11596-022-2663-8

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  • DOI: https://doi.org/10.1007/s11596-022-2663-8

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