VAMP8 as a biomarker and potential therapeutic target for endothelial cell dysfunction in atherosclerosis.

Background: Endothelial cell dysfunction has a critical role in the pathophysiology of atherosclerosis. This study aims to uncover pivotal genes and pathways linked to endothelial cell dysfunction in atherosclerosis, as well as to ascertain the assumed causal effects and potential mechanisms.

Methods: Datasets relevant to endothelial cell dysfunction in atherosclerosis were collected and divided into training and validation sets. Following differential analysis, we constructed a protein-protein interaction (PPI) network and a molecular interaction map of common-differentially expressed genes (co-DEGs) with proteins known to be involved in atherosclerotic endothelial cell dysfunction. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genome (KEGG), and Gene Set Enrichment Analysis (GSEA) were also conducted. Moreover, human umbilical vascular endothelial cells (HUVECs) were cultured in circumstances characterized by elevated glucose levels to establish a cellular injury model simulating atherosclerotic conditions, and quantitative Polymerase Chain Reaction (qPCR) experiments were conducted to validate the differences of co-DEGs. Subsequently, the Summary-data-based Mendelian Randomization (SMR) method was employed. Additionally, we employed the Western Blot (WB) technique to validate the differential expression of VAMP8. Finally, we identified the differential expression of VAMP8 in the validation set and further validated its differential expression by collecting fresh blood samples from 20 patients with atherosclerosis and 20 healthy individuals.

Results: 14 co-DEGs (FABP5, GULP1, COL4A5, VAMP8, FABP4, PFN2, ANGPT2, TFPI2, NUPR1, SULF1, FGF13, BASP1, EPB41L3, and PBK) were identified. SMR analysis confirmed 10 potential causal effect genes: PSRC1, VAMP8, FES, HNRNPUL1, CFDP1, SAP130, MDN1, OPRL1, UTP11, and HOXC4. The qPCR and WB experiments demonstrated that VAMP8 was significantly upregulated in the injured HUVECs group (p < 0.0001). Compared to the control group, VAMP8 was markedly increased in the blood samples of patients with atherosclerosis (p < 0.0001).

Conclusions: VAMP8 may potentially serve as a pathogenic gene in the process of endothelial dysfunction in atherosclerosis.