Blocking circ_UBR4 suppressed proliferation, migration, and cell cycle progression of human vascular smooth muscle cells in atherosclerosis

Abstract

The circ_UBR4 (hsa_circ_0010283) is a novel abnormally overexpressed circRNA in oxidized low-density lipoprotein (ox-LDL)-induced model of atherosclerosis (AS) in human vascular smooth muscle cells (VSMCs). However, its role in the dysfunction of VSMCs remains to be further investigated. Here, we attempted to explore its role in ox-LDL-induced excessive proliferation and migration in VSMCs by regulating Rho/Rho-associated coiled-coil containing kinase 1 (ROCK1), a therapeutic target of AS. Expression of circ_UBR4 and ROCK1 was upregulated, whereas miR-107 was downregulated in human AS serum and ox-LDL-induced VSMCs. Depletion of circ_UBR4 arrested cell cycle, suppressed cell viability, colony-forming ability, and migration ability, and depressed expression of proliferating cell nuclear antigen and matrix metalloproteinase 2 in VSMCs in spite of the opposite effects of ox-LDL. Notably, ROCK1 upregulation mediated by plasmid transfection or miR-107 deletion could counteract the suppressive role of circ_UBR4 knockdown in ox-LDL-induced VSMCs proliferation, migration, and cell cycle progression. In mechanism, miR-107 was identified as a target of circ_UBR4 to mediate the regulatory effect of circ_UBR4 on ROCK1. circ_UBR4 might be a contributor in human AS partially by regulating VSMCs’ cell proliferation, migration, and cell cycle progression via circ_UBR4/miR-107/ROCK1 pathway.

A Novel circUBR4/miR-491-5p/NRP2 ceRNA Network Regulates Oxidized Low-density Lipoprotein-induced Proliferation and Migration in Vascular Smooth Muscle Cells

“…12,36,37 Because of the significant overexpression of circUBR4 in ox-LDL-treated VSMCs, 16 we focused on the ceRNA role of circUBR4 in regulating VSMC migration and proliferation stimulated by ox-LDL. Zhang et al 17 identified that circUBR4 acted as a regulator of VSMC proliferation and migration under ox-LDL by binding to miR-107 to induce ROCK1. Ding et al 19 underscored the regulation of circUBR4 in ox-LDL-evoked VSMC migration and proliferation depending on the modulation of miR-370-3p/HMGB1 axis.…”

“…Previous evidence also indicated that NRP2 functioned as a downstream effector of the circCHFR/ miR-149-5p axis in regulating VSMC migration and proliferation. 31 Recent evidence has uncovered 3 ceRNA networks in the regulation of circUBR4, including the circUBR4/miR-107/ROCK1, 17 circUBR4/miR-370-3p/HMGB1, 19 and circUBR4/miR-133a-3p/PAPPA, 18 in VSMC migration and invasion. The 4 ceRNA axes (including our findings) may be 4 paralleled or interactional networks for the regulation of circUBR4.…”

“…16 Emerging evidence also highlights the overexpression of circUBR4 in atherosclerosis serum and the profound regulation of circUBR4 in VSMC migration and proliferation evoked by ox-LDL. 17–19…”

“…16 Emerging evidence also highlights the overexpression of circUBR4 in atherosclerosis serum and the profound regulation of circUBR4 in VSMC migration and proliferation evoked by ox-LDL. [17][18][19] Deregulated miRNAs have been implicated in the progression of atherosclerosis 20 and the regulation of VSMC migration and proliferation. [21][22][23] A previous report demonstrated that miR-491-5p was associated with the low risk of atherosclerotic cerebral infarction.…”

Hsa_circ_0001879 promotes the progression of atherosclerosis by regulating the proliferation and migration of oxidation of low density lipoprotein (ox-LDL)-induced vascular endothelial cells via the miR-6873-5p-HDAC9 axis

“…Hsa_circ_0001445 reverses ox-LDL‑induced inhibition of HUVEC proliferation by targeting SRSF1 [ 8 ]. Inhibiting circ_UBR4 (hsa_circ_0010283) suppressed the proliferation, migration, and cell cycle progression of human vascular smooth muscle cells and promotes the progression of AS [ 9 ]. Circ_0004104 protects vascular endothelial cells from low-density lipoprotein-induced dysfunction by targeting the miR-328-3p/TRIM14 axis [ 10 ].…”