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All-Trans Retinoic Acid Prevented Vein Grafts Stenosis by Inhibiting Rb-E2F Mediated Cell Cycle Progression and KLF5-RARα Interaction in Human Vein Smooth Muscle Cells

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Abstract

Purpose

Vein graft failure (VGF) is an important limitation for coronary artery bypass graft (CABG) surgery. Inhibition of the excessive proliferation and migration of venous smooth muscle cells (SMCs) is an effective strategy to alleviate VGF during the CABG perioperative period. In the present study, we aimed to explore the role and potential mechanism of all-trans retinoic acid (ATRA) on preventing vein grafts stenosis.

Methods

The autogenous vein grafts model was established in the right jugular artery of rabbits. Immunohistochemistry staining and western blot assays were used to detected the protein expression, while real-time PCR assay was applied for mRNAs expression detection. The interaction between proteins was identified by co-immunoprecipitation assay. The Cell Counting Kit-8 and wound-healing assays were used to investigate the role of ATRA on human umbilical vein smooth muscle cells (HUVSMCs) function. Cell cycle progression was identified by flow cytometry assay.

Results

Vein graft stenosis and SMCs hyperproliferation were confirmed in vein grafts by histological and Ki-67 immunohistochemistry assays. Treatment of ATRA (10 mg/kg/day) significantly mitigated the stenosis extent of vein grafts, demonstrated by the decreased thickness of intima-media, and decreased Ki-67 expression. ATRA could repress the PDGF-bb-induced excessive proliferation and migration of HUVSMCs, which was mediated by Rb-E2F dependent cell cycle inhibition. Meanwhile, ATRA could reduce the interaction between KLF5 and RARα, thereby inhibiting the function of cis-elements of KLF5. KLF5-induced inducible nitric oxide synthase (iNOS) expression activation could be significantly inhibited by ATRA.

Conclusions

These results suggested that ATRA treatment may represent an effective prevention and therapy avenue for VGF.

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Funding

This work was supported by the National Natural Science Foundation of China (81470592 and 81800341) and the Science Foundation of Shanghai Municipal Health Planning Commission (20164Y0277).

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Author notes

  1. Yongchao Yu, Yang Wang and Xiang Fei contributed equally to this work.

Authors and Affiliations

  1. Institute of Cardiac Surgery, Department of Cardiovascular Surgery, Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China

    Yongchao Yu, Yang Wang, Xiang Fei, Zhigang Song, Feng Xie, Fan Yang, Xiaohong Liu, Zhiyun Xu & Guokun Wang

  2. National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, 210018, China

    Yang Wang

Authors
  1. Yongchao Yu
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  2. Yang Wang
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  3. Xiang Fei
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  4. Zhigang Song
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  5. Feng Xie
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  6. Fan Yang
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  7. Xiaohong Liu
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Contributions

Z.X., G. W., and X. L. conceived and designed the experiments. Y. Y., Y. W., and X. F. performed the experiments. Y. Y., Z. S., and F. X. analyzed and confirmed the data. F. Y. performed the statistical analysis. G. W. and Y. Y. wrote the manuscript.

Corresponding authors

Correspondence to Xiaohong Liu, Zhiyun Xu or Guokun Wang.

Ethics declarations

All animal procedures were approved by the Animal Ethics Committee of Changhai Hospital, Naval Medical University. All experiments were performed in strict compliance with requirements of the Animal Ethics Procedures and Guidelines of China.

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The authors declare no conflict of interest.

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Yu, Y., Wang, Y., Fei, X. et al. All-Trans Retinoic Acid Prevented Vein Grafts Stenosis by Inhibiting Rb-E2F Mediated Cell Cycle Progression and KLF5-RARα Interaction in Human Vein Smooth Muscle Cells. Cardiovasc Drugs Ther 35, 103–111 (2021). https://doi.org/10.1007/s10557-020-07089-4

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  • DOI: https://doi.org/10.1007/s10557-020-07089-4

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