Cathepsin S are involved in human carotid atherosclerotic disease progression, mainly by mediating phagosomes: bioinformatics and in vivo and vitro experiments

Hailong Wang; Haiying Jiang; Xian Wu Cheng

doi:10.7717/peerj.12846

Cathepsin S are involved in human carotid atherosclerotic disease progression, mainly by mediating phagosomes: bioinformatics and in vivo and vitro experiments

PeerJ. 2022 Feb 8:10:e12846. doi: 10.7717/peerj.12846. eCollection 2022.

Authors

Hailong Wang^#^{1

2}, Haiying Jiang³, Xian Wu Cheng^#^{1

2}

Affiliations

¹ Department of Cardiology and Hypertension, Yanbian University Hospital, Yanji, Jilin, China.
² Department of Community Health & Geriatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
³ Department of Department of Physiology and Pathophysiology, Jiaxing University Medical College, Jiaxing, Zhejiang, China.

^# Contributed equally.

Abstract

Background: Atherosclerosis emerges as a result of multiple dynamic cell processes including endothelial damage, inflammatory and immune cell infiltration, foam cell formation, plaque rupture, and thrombosis. Animal experiments have indicated that cathepsins (CTSs) mediate the antigen transmission and inflammatory response involved in the atherosclerosis process, but the specific signal pathways and target cells of the CTSs involved in atherosclerosis are unknown.

Methods: We used the GEO query package to download the dataset GSE28829 from the Gene Expression Omnibus (GEO) and filtered the data to check the standardization of the samples through the box chart. We then used the 'limma' package to analyze between-group differences and selected the corresponding differentially expressed genes of CTSs from the protein-protein interaction (PPI) network constructed with the STRING database, and then visualized the CTS-target genes. The best matching pathway and target cells were verified by a male mouse ligation experiment, single-sample GSEA (ssGSEA) analysis, and vitro experiment.

Results: There were 275 differentially expressed genes (DEGs) selected from the GSE28829 dataset, and the DEGs were identified mainly in the PPI network; 58 core genes (APOE, CD74, CP, AIF1, etc.) target three selected CTS family members (CTSS, CTSB, and CTSC). After the enriched analysis, 15 CTS-target genes were markedly enriched in the phagosome signaling pathway. The mouse experiment results revealed that the percentages and numbers of monocytes and neutrophils and the number of CD68⁺ cells in CTSS deficiency (CatS^-/-) group were lower than those in the wildtype (CatS^+/+) group. CTSS mediating phagosome via macrophage were further verified by ssGSEA analysis and vitro experiment.

Conclusions: CTSS are the main target molecules in the CTS family that are involved in atherosclerosis. The molecule participate in the progression of atherosclerosis by mediating the phagosome via macrophage.

Keywords: Atherosclerosis; Bioinformatics; Cathepsin S; Macrophage; Phagosome.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Atherosclerosis* / genetics
Carotid Artery Diseases* / genetics
Cathepsins / genetics
Computational Biology / methods
Humans
Male
Mice
Phagosomes / metabolism

Substances

cathepsin S
Cathepsins

Grants and funding

This work was supported by grants from the National Natural Science Foundation of China (Nos. 81560240 and 81770485) and The Ministry of Education, Culture, Sports, Science and Technology of Japan (Nos. 24659385 and 15H04802). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.