Circ_UBR4 Knockdown Alleviates Oxidized Low-Density Lipoprotein-Provoked Growth and Migration of Human Vascular Smooth Muscle Cells by Acting on the miR-637/FOXO4 Pathway.

Abstract

Excessive proliferation and migration of human vascular smooth muscle cells (HVSMCs) induced by oxidized low-density lipoprotein (ox-LDL) are important pathological features of atherosclerosis. Emerging evidence indicates that circular RNAs deregulation is involved in this pathological process. The objective of this study was to explore the role of circular RNA ubiquitin protein ligase E3 component n-recognin 4 (circ_UBR4) in ox-LDL-treated HVSMCs. The expression of circ_UBR4, microRNA-637 (miR-637), and forkhead box O4 (FOXO4) mRNA was detected by quantitative real-time PCR. Cell cycle progression was examined by flow cytometry assay. Cell viability was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell migration was examined by transwell assay. The protein levels of proliferating cell nuclear antigen, matrix metalloproteinase 2, and FOXO4 were measured by western blot. The relationship between miR-637 and circ_UBR4 or FOXO4 was confirmed by dual-luciferase reporter assay. The results presented that the expression of circ_UBR4 was increased in atherosclerosis serum samples and ox-LDL-treated HVSMCs. Cell cycle progression, cell proliferation, and cell migration were promoted by ox-LDL, whereas circ_UBR4 knockdown inhibited HVSMCs proliferation and migration. MiR-637 was a target of circ_UBR4, and FOXO4 was a target of miR-637. Circ_UBR4 positively regulated FOXO4 expression by targeting miR-637. Circ_UBR4 knockdown-inhibited HVSMCs proliferation and migration were recovered by miR-637 inhibition, and miR-637 restoration-inhibited HVSMCs proliferation and migration were recovered by FOXO4 overexpression. In conclusion, circ_UBR4 knockdown inhibited ox-LDL-induced excessive proliferation and migration of HVSMCs by regulating FOXO4 via targeting miR-637.