Hsa_circ_0087352 promotes the inflammatory response of macrophages in abdominal aortic aneurysm by adsorbing hsa-miR-149-5p

Abstract

Abdominal aortic aneurysms (AAA) is a common cardiovascular disease with the risk of rupture. Macrophage depletion can significantly limit the formation of experimental AAA. However, how macrophages in the arterial wall affect the focal distribution and progression of AAA remains unclear. Here, we aimed to evaluate whether circRNAs characterized by stable structure and high tissue specific expression can regulate the inflammatory response of macrophages in AAA. First, we applied bioinformatics to analyze circRNA expression profile in human AAA specimens, and screened out hsa_circ_0087352, which is up-regulated in human AAA specimens and related to inflammatory response of THP-1 macrophages induced by LPS. Besides, hsa_circ_0087352 is stably expressed in THP-1 and mainly distributed in the nucleus. Then, we constructed ceRNA network of circRNA-miRNA-mRNA (IL-6/CCL2/NF-κB) in AAA and found that hsa_circ_0087352 promotes IL-6 transcription and the secretion of inflammatory cytokines by sponging endogenous hsa-miR-149-5p in macrophages. Dual luciferase reporter gene and RNA pull-down suggested hsa_circ_0087352 directly binds to hsa-miR-149-5p. Fluorescence in situ hybridization assay showed the localization of hsa_circ_0087352 and hsa-miR-149-5p in the nucleus of macrophages. Further, western blot demonstrated hsa_circ_0087352 expands the signal transduction of ERK/NF-κB pathway, then IκB phosphorylation promotes NF-κB p65 phosphorylation and nuclear translocation. In addition, hsa_circ_0087352 overexpression in macrophages induces human vascular smooth muscle cells (VSMC) apoptosis in macrophage-VSMC coculture system via the release of proapoptotic cytokines, such as IL-6, TNF-α and IL-1β. Overall, this study provides experimental evidence that hsa_circ_0087352 can be used as a new biomarker and therapeutic target for abdominal aortic aneurysm.