https://orcid.org/0000-0001-7771-5483
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Abstract
Purpose
Immune microenvironment plays an important role in aortic dissection (AD). Therefore, novel immune biomarkers may facilitate AD prevention, diagnosis, and treatment. This study aimed at mining key immune-related genes and relevant mechanisms involved in AD pathogenesis.
Patients and Methods
Key immune cells in AD were identified by ssGESA algorithm. Next, genes associated with key immune cells were screened by weighted gene coexpression network analysis (WGCNA). Then hub immune genes were picked from protein-protein interaction network of overlapped genes from differential expression and WGCNA analyses by cytohubba plug-in. Their diagnostic potential was evaluated in two independent cohorts from GEO database. In addition, the expressions of hub immune genes were determined by quantitative RT-PCR, immunohistochemistry, and Western blotting in dissected and normal aortic tissues.
Results
Activated B cells, CD56dim natural killer cells, eosinophils, gamma delta T cells, immature B cells, natural killer cells and type 17 T helper cells were identified as key immune cells in AD. Thereafter, a gene module significantly correlated with key immune cells were found by WGCNA method. Subsequently, KDR, IGF1, NOS3, PECAM1, GAPDH, FLT1, DLL4, CDH5, VWF, and TEK were identified as hub immune cell related genes by PPI network analysis, which may be potential diagnostic markers for AD, as evidenced by ROC curves. Moreover, the decreased expression of VWF in AD was validated at both mRNA and protein levels, and its expression was significantly positive correlated with the marker of smooth muscle cells, ACTA2, in AD. Further immunofluorescent results showed that VWF was colocalized with ACTA2 in aortic tissues.
Conclusion
We identified key immune cells and hub immune cell-related genes involved in AD. Moreover, we found that VWF was co-expressed with the smooth muscle cell marker ACTA2, indicating the important role of VWF in smooth muscle cell loss in AD pathogenesis.
Abbreviations
DIIC, differentially infiltrated immune cells; AD, aortic dissection; GEO, gene expression omnibus; DEGs, differentially expressed genes; WGCNA, weighted gene coexpression network analysis; PPI, protein-protein interaction; CTA, computed tomographic angiography; MM, module membership; GS, gene significance; TF, transcription factor; H&E, hematoxylin and eosin; KDR, kinase insert domain receptor; IGF1, insulin-like growth factor 1; NOS3, nitric oxide synthase 3; PECAM1, platelet and endothelial cell adhesion molecule 1; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; FLT1, Fms-related receptor tyrosine kinase 1; DLL4, delta-like canonical notch ligand 4; CDH5, cadherin 5; VWF, von Willebrand factor; TEK, TEK receptor tyrosine kinase.
Data Sharing Statement
The datasets used in this study were downloaded from the GEO database. Further inquiries can be directed to the corresponding authors.
Ethics Approval and Informed Consent
This study was conducted in accordance with the principles of the Declaration of Helsinki. This study was approved by the Ethics Committee of the Second Hospital of Shanxi Medical University. Informed consent was obtained from all subjects involved in the study.
Acknowledgments
The authors thank BIOINFOR-MEDICAL CENTRE at the Second Hospital of Shanxi Medical University for their academic instruction and manuscript revision.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
The authors report no conflicts of interest in this work.