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Updated: Jul 6, 2025
On-Chip Endothelial Inflammatory Phenotyping
Published on: July 21, 2012
Integrative analysis reveals chemokines CCL2 and CXCL5 mediated shear stress-induced aortic dissection formation
Chao Xue1, Liqing Jiang1, Bin Zhang1
1Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
Insights
This study reveals that shear stress contributes to aortic dissection (AD) by involving specific molecules like CCL2 and CXCL5. These findings identify potential therapeutic targets for preventing and treating this critical cardiovascular condition.
Area of Science:
- Cardiovascular Biology
- Bioinformatics
- Molecular Medicine
Background:
- Aortic dissection (AD) is a life-threatening cardiovascular emergency.
- The role of varying shear stress in AD pathogenesis is under-investigated.
- This study explores molecular mechanisms of shear stress-induced AD.
Purpose of the Study:
- To identify key molecules involved in shear stress-induced AD.
- To investigate potential therapeutic agents for AD.
- To validate findings using clinical tissue samples.
Main Methods:
- Quantitative bioinformatic analysis of public RNA sequencing datasets (GSE153434, GSE147026, GSE52093, GSE160611).
- Identification and integration of differentially expressed genes (DEGs).
- Network analysis (STRING, Cytoscape, MCODE) and Connectivity Map (CMap) analysis.
- Validation using immunoblotting, immunofluorescence, and single-cell sequencing data.
Main Results:
- Identified common DEGs in AD related to blood vessel morphogenesis and chemotaxis.
- MYC, CCL2, and SPP1 identified as key hub molecules in AD.
- Five shear stress-associated hub DEGs in AD (ANGPTL4, SNAI2, CCL2, GADD45B, PROM1) linked to endothelial cell apoptosis.
- CCL2 and CXCL5 expression confirmed in clinical AD tissues; CCL2 and CXCL5 identified as key chemokines.
- MEK and ALK inhibitors suggested as potential therapeutic agents.
Conclusions:
- Integrative analysis identified core DEGs and potential therapeutic agents for AD.
- The CCL2 and CXCL5-mediated "Endothelial-Monocyte-Neutrophil" axis is implicated in shear stress-induced AD.
- Findings offer novel therapeutic targets for AD prevention and treatment.
Background:
Aortic dissection (AD) is a critical emergency in cardiovascular disease. AD occurs only in specific sites of the aorta, and the variation of shear stress in different aortic segments is a possible cause not reported. This study investigated the key molecules involved in shear stress-induced AD through quantitative bioinformatic analysis of a public RNA sequencing database and clinical tissue sample validation.
Methods:
Gene expression data from the GSE153434, GSE147026, and GSE52093 datasets were downloaded from the Gene Expression Omnibus. Next, differently expressed genes (DEGs) in each dataset were identified and integrated to identify common AD DEGs. STRING, Cytoscape, and MCODE were used to identify hub genes and crucial clustering modules, and Connectivity Map (CMap) was used to identify positive and negative agents. The same procedure was performed for the GSE160611 dataset to obtain shear stress-induced human aortic endothelial cell (HAEC) DEGs. After the integration of these two DEGs sets to identify shear stress-associated hub DEGs in AD, Gene Ontology Enrichment Analysis was performed. The common chemokine receptors and ligands in AD were identified by analyzing AD's three RNA sequencing datasets. Their origin was verified by analyzing AD single-cell sequencing data and validated by immunoblotting and immunofluorescence.
Results:
We identified 100 down-regulated and 50 up-regulated AD common DEGs. Enrichment results showed that common DEGs were closely related to blood vessel morphogenesis, muscle structure development, muscle tissue development, and chemotaxis. Among those DEGs, MYC, CCL2, and SPP1 are the three molecules with the highest degree. A crucial cluster of 15 genes was identified using MCODE, which contained inflammation-related genes with elevated expression and muscle cell-related genes with decreased expression, and CCL2 is central to immune-related genes. CMap confirmed MEK inhibitors and ALK inhibitors as possible therapeutic agents for AD. Moreover, 366 shear stress-associated DEGs in HAEC were identified in the GSE160611 dataset. After taking the intersection, we identified five shear stress-associated hub DEGs in AD (ANGPTL4, SNAI2, CCL2, GADD45B, and PROM1), and the enrichment analysis indicated they were related to the endothelial cell apoptotic process. Chemokine CCL2 was the molecule with a high degree in both DEG sets. Besides CCL2, CXCL5 was the only chemokine ligand differentially expressed in the three datasets. Additionally, immunoblotting confirmed the increased expression of CCL2 and CXCL5 in clinical tissue samples. Further research at the single-cell level revealed that CCL2 has multiple origins, and CXCL5 is macrophage-derived.
Conclusion:
Through integrative analysis, we identified core common AD DEGs and possible therapeutic agents based on these DEGs. We elucidated that the chemokine CCL2 and CXCL5-mediated "Endothelial-Monocyte-Neutrophil" axis may contribute to the development of shear stress-induced AD. These findings provide possible therapeutic targets for the prevention and treatment of AD.
