miR-33-5p knockdown attenuates abdominal aortic aneurysm progression via promoting target adenosine triphosphate-binding cassette transporter A1 expression and activating the PI3K/Akt signaling pathway

Abstract

Purpose: The aim of this study was to investigate the role of miR-33-5p in abdominal aortic aneurysm progression, which regulated adenosine triphosphate-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux and lipid accumulation in THP-1 macrophage-derived foam cells through the PI3K/Akt pathway. Methods: Quantitative reverse transcription polymerase chain reaction was used to evaluate the expression level of miR-33-5p and ABCA1 mRNA in abdominal aortic aneurysm patient and normal person tissues. The relationship between miR-33-5p and ABCA1 was examined by dual luciferase report assay. High-performance liquid chromatography was used to evaluate the levels of cholesterol contents. Cholesterol efflux detection was performed by liquid scintillator. The expression of inflammatory cytokines was detected by quantitative reverse transcription polymerase chain reaction. Western blot was applied to determine the expression levels of ABCA1, PI3K (p-PI3K), and Akt (p-Akt). Results: The quantitative reverse transcription polymerase chain reaction analysis results revealed miR-33-5p overexpression in abdominal aortic aneurysm tissues, but the expression level of ABCA1 was lower in abdominal aortic aneurysm tissues than non-abdominal aortic aneurysm tissues. Subsequently, the dual luciferase report gene assay confirmed that ABCA1 was a target of miR-33-5p, and miR-33-5p-negative regulated ABCA1 expression. Moreover, the expression levels of p-PI3K, p-Akt, and ABCA1 were decreased in THP-1 cell transferred with ABCA1 siRNA, but knockdown of miR-33-5p had an opposite effect. Furthermore, knockdown of miR-33-5p decreased the expression of MMP-2, MMP-9, TNF-α, total cellular cholesterol, and promoted cholesterol efflux in THP-1-derived foam cells. Importantly, LY294002 (PI3K inhibitor) or si-ABCA1 completely inhibited the stimulatory effects of miR-33-5p inhibitor. Conclusion: This study has found that knockdown of miR-33-5p induced ABCA1 expression and promoted inflammatory cytokines and cholesterol efflux likely via activating the PI3K/Akt signaling pathway.

hsa-miR-33-5p as a Therapeutic Target Promotes Apoptosis of Breast Cancer Cells via Selenoprotein T

“…As previously reported, hsa-miR-33-5p could induce osteoblast differentiation through targeting Hmga2 (22,24). Its knockdown could inhibit abdominal aortic aneurysm development through ABCA1 expression and activation of the PI3K/Akt pathway (25). Lowly expressed hsa-miR-33-5p is involved in inhibiting the apoptosis of murine dorsal root ganglion neurons (26).…”

MicroRNA-33-5p inhibits cholesterol efflux in vascular endothelial cells by regulating citrate synthase and ATP-binding cassette transporter A1

“…ABCA1 is a direct target of miR-33-5p [ 14 , 20 ]. Knockdown of miR-33-5p has been reported to decrease the levels of TC and TNF-α, and promote cholesterol efflux from macrophage-derived foam cells [ 20 ]. Our present study demonstrated the targeted interaction that occurs between ABCA1 and miR-33-5p.…”

“…In addition, ABCA1 also promotes the production of athero-protective HDL cholesterol [ 18 , 19 ]. MiR-33-5p targets ABCA1, and knockdown of miR-33-5p decreases the levels of total cholesterol (TC) and TNF-α, and promotes cholesterol efflux from foam cells [ 13 , 20 ]. It has been reported that the inflammatory cytokines IL-6 and TNF-α can suppress ABCA1 expression and thereby inhibit cholesterol efflux [ 17 ].…”

Genomic Variants and Multilevel Regulation of ABCA1, ABCG1, and SCARB1 Expression in Atherogenesis

“…In humans, there are two isoforms, miR-33a and miR-33b; in mice, there is only one isoform of miR-33, homologous to human miR-33a [212]. In mice, human hepatocytes, macrophages, and some other cells, miR-33 suppress ABCA1 expression by directly binding to sites in 3 -UTR [212][213][214][215]. As a result, the cholesterol efflux from cells to the ApoA-I protein is suppressed.…”