Zhang Ying, Zhang Cheng, Chen Zongwei, Wang Meilan
Department of Cardiology, Zhongshan Affiliated Hospital, Dalian University, No. 6, Zhonshan Road, Dalian, 116001, Liaoning, China.
Open Life Sci. 2021 Apr 27;16(1):419-430. doi: 10.1515/biol-2021-0044. eCollection 2021.
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.
环 UBR4（hsa_circ_0010283）是一种新型的异常过表达的环状 RNA，在氧化型低密度脂蛋白（ox-LDL）诱导的人血管平滑肌细胞（VSMC）动脉粥样硬化（AS）模型中存在。然而，其在 VSMC 功能障碍中的作用仍有待进一步研究。在此，我们试图通过调节 Rho/与 Rho 相关的卷曲螺旋蛋白激酶 1（ROCK1，AS 的一个治疗靶点）来探讨其在 ox-LDL 诱导的 VSMC 过度增殖和迁移中的作用。在人 AS 血清和 ox-LDL 诱导的 VSMC 中，环 UBR4 和 ROCK1 的表达上调，而 miR-107 的表达下调。环 UBR4 的缺失使细胞周期停滞，抑制细胞活力、集落形成能力和迁移能力，并降低 VSMC 中增殖细胞核抗原和基质金属蛋白酶 2 的表达，尽管 ox-LDL 有相反的作用。值得注意的是，质粒转染介导的 ROCK1 上调或 miR-107 的缺失可抵消环 UBR4 敲低对 ox-LDL 诱导的 VSMC 增殖、迁移和细胞周期进程的抑制作用。在机制上，miR-107 被确定为环 UBR4 的靶点，以介导环 UBR4 对 ROCK1 的调节作用。环 UBR4 可能部分通过 circ_UBR4/miR-107/ROCK1 途径调节 VSMC 的细胞增殖、迁移和细胞周期进程，从而在人类 AS 中发挥作用。
