LncRNA-ADAM11 regulates the vascular endothelial cell senescence and promotes the development of intracranial aneurysm via MiR-223-3p/NLRP3 pathway

Abstract

Intracranial aneurysms (IAs) are the localized dilatations of intracranial arteries because of the weaknesses of the endothelial layer. It causes subarachnoid hemorrhage (SAH), which accounted for 80% of total SAH and has 50% fatality rate. Cell senescence, especially endothelial cells senescence, is closely related to the occurrence of vascular diseases. However, the relationship of endothelial cell senescence and IAs have not well defined. It is reported that circulating exosomes and exosomes-derived lncRNAs involved in the process of various diseases. LncRNAs expression aberrant in serum and IAs tissues from IA patients has been confirmed. However, the relationship of serum exosomes-derived lncRNAs and endothelial cell senescence in IAs has unclearly. Therefore, the current study aims to investigate the roles and underlying mechanisms of circulating exosomes-derived lncRNA in the senescent endothelial cells of IAs. In this study, we used ligation operation to construct IA rats. We also isolated and cultured endothelial cells from rat’s ACA/OA bifurcation. The blood pressure was detected to confirm the IA rats construction. HE staining and SA-β-gal staining was used to detect the pathologic of aneurysm and cell senescence. The expression of senescence marker genes and NLRP3 inflammasome-related genes was detected by western blot. ELISA was used to detect the expression levels of inflammatory factor. Immunofluorescence was used to confirm the cell type of senescence. Differential expression lncRNAs were identified by RNA sequencing in exosomes from clinical samples. Exosomes-derived lncRNA function was confirmed through co-culture and overexpression or knockdown lncRNA. Luciferase reporter assay and RIP assay confirmed the target binding of miRNA and lncRNA. Rescue experiments were performed to confirm lncRNA-miRNA-mRNA mechanism in endothelial cell senescence. The present study found that NLRP3 involved in the process of endothelial cell senescence in IAs. Exosomes from IA patient’s peripheral blood promoted endothelial cells senescence through transferring lncRNA ADAM11. In mechanism, lncADAM11 promoted endothelial cells senescence through competing bind to miR-223-3p and further promoting the expression of NLRP3. In conclusion, circulating exosomes-derived lncRNA ADAM11 regulated the senescence of vascular endothelial cells and promoted the development of IA via miR-223-3p/NLRP3 axis.