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P-Selectin Glycoprotein Ligand-1 Deficiency Protects Against Aortic Aneurysm Formation Induced by DOCA Plus Salt

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Abstract

Purpose

P-selectin glycoprotein ligand-1 (PSGL-1) acts as a crucial regulator for the inflammatory cells infiltration by mediating the adhesion of leukocytes. However, the role of PSGL-1 in aortic aneurysm remains elusive. Here, we investigated the role of PSGL-1 in aortic aneurysm (AA) development.

Methods

We first detected PSGL-1 expression in samples from aortic aneurysm patients and mouse AA models via western blotting, immunofluorescence, and flow cytometry, and then we used global PSGL-1 knockout mice and their wild type controls to establish an aortic aneurysm model induced by deoxycorticosterone acetate (DOCA) plus high salt (HS). The incidence, fatality rates, and the pathological changes of aortic aneurysm were analyzed in each group. The inflammation, adhesion molecules expression, and PSGL-1 mediated leukocyte–endothelial adhesion and their underlying mechanisms were explored further.

Results

Increased PSGL-1 levels were observed in human and mouse aortic aneurysm, and on leukocytes of mice treated with DOCA+HS. PSGL-1 deficiency reduced the incidence and severity of aortic aneurysm significantly, as well as decreased elastin fragmentation, collagen accumulation, and smooth muscle cells degeneration. Mechanistically, the protective effect of PSGL-1 inhibition was mediated by the reduced adhesion molecules, and the subsequently reduced leukocyte–endothelial adhesion through the NF-κB pathway, which finally led to reduced inflammatory cells infiltration and decreased inflammatory factors expression.

Conclusion

PSGL-1 deficiency is protective against inflammatory cells migration and recruitment in the condition of AA through attenuation of leukocyte–endothelial adhesion. Inhibition of PSGL-1 may be a potential therapeutic target for the prevention and treatment of human AA.

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Data Availability

All data involved in this study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by grants from the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (CIFMS, 2016-I2M-1-016, 2019-I2M-1-001); National Natural Science Foundation of China (81800402, 81670387); Fundamental Research Funds for the Central Universities (3332018107); and Life science society consortium “Youth Talent Promotion Project.”

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Authors and Affiliations

  1. Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS) & Comparative Medicine Centre, Peking Union Medical College (PUMC), 5 Pan Jia Yuan Nan Li Chaoyang District, Beijing, 100021, People’s Republic of China

    Xianxian Wu, Xing Liu, Xue Liu, Xiaoliang Jiang & Zhiwei Yang

  2. State Key Laboratory of Cardiovascular Disease, Beijing Key Laboratory for Molecular Diagnostics of Cardiovascular Diseases, Diagnostic Laboratory Service, Center of Laboratory Medicine, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China

    Hang Yang, Qianlong Chen & Zhou Zhou

  3. Institute of Cardiovascular Diseases, General Hospital of Ningxia Medical University, Yinchuan, 750001, Ningxia, China

    Na Zhang

  4. School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China

    Yuhan Li, Xingchen Du & Yideng Jiang

Authors
  1. Xianxian Wu
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  2. Xing Liu
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  3. Hang Yang
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  11. Zhou Zhou
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Contributions

Zhiwei Yang and Xianxian Wu designed the study. Xianxian Wu, Xing Liu, Hang Yang, Qianlong Chen, Na Zhang, Yuhan Li, Xingchen Du, Xue Liu, and Xiaoliang Jiang carried out data acquisition and analysis. Xianxian Wu and Zhiwei Yang wrote the paper. Yideng Jiang and Zhou Zhou supervised the study. All authors reviewed the manuscript.

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Correspondence to Zhou Zhou or Zhiwei Yang.

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Wu, X., Liu, X., Yang, H. et al. P-Selectin Glycoprotein Ligand-1 Deficiency Protects Against Aortic Aneurysm Formation Induced by DOCA Plus Salt. Cardiovasc Drugs Ther 36, 31–44 (2022). https://doi.org/10.1007/s10557-020-07135-1

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