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Circ_0020397 通过 miR-502-5p 上调 GREM1 表达来调节颅内动脉瘤中血管平滑肌细胞的活力。

Circ_0020397 regulates the viability of vascular smooth muscle cells by up-regulating GREM1 expression via miR-502-5p in intracranial aneurysm.

机构信息

Department of Neurosurgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.

Department of Neurosurgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.

出版信息

Life Sci. 2021 Jan 15;265:118800. doi: 10.1016/j.lfs.2020.118800. Epub 2020 Nov 23.

Abstract

AIMS

Circ_0020397 has been found to be down-regulated in intracranial aneurysm (IA), and deregulation of circ_0020397 involved in the regulation of vascular smooth muscle cells (VSMCs) proliferation. However, the mechanism by which circ_0020397 implicates in VSMC dysfunction in IA remains vague.

MATERIALS AND METHODS

The expression of circ_0020397, miR-502-5p and Gremlin 1 (GREM1) was detected using quantitative real-time polymerase chain reaction. Cell viability was analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Protein levels of proliferating cell nuclear antigen (PCNA) and GREM1 were measured using western blot. The interaction between miR-502-5p and circ_0020397 or GREM1 was confirmed by dual-luciferase reporter, RNA pull-down and RNA immunoprecipitation assay.

KEY FINDINGS

Circ_0020397 or GREM1 expression was decreased in VSMCs isolated from IA patients, and overexpression of circ_0020397 or GREM1 promoted VSMC viability and elevated PCNA expression level, while inhibition of them showed opposite effects. MiR-502-5p was confirmed to directly bind to circ_0020397 or GREM1, and miR-502-5p reversed the effects of circ_0020397 on VSMC viability and PCNA level. Besides, miR-502-5p overexpression suppressed VSMC viability and reduced PCNA level, while these effects were attenuated by GREM1 up-regulation. Importantly, circ_0020397 could regulate GREM1 expression via miR-502-5p in VSMCs.

SIGNIFICANCE

Circ_0020397 played an important role in phenotypic modulation in IA by promoting VSMC viability via miR-502-5p/GREM1 axis, suggesting a novel insight into IA pathogenesis and new targets for IA molecular therapy.

摘要

目的

Circ_0020397 在颅内动脉瘤(IA)中表达下调,Circ_0020397 失调参与血管平滑肌细胞(VSMCs)增殖的调节。然而,Circ_0020397 如何参与 IA 中 VSMC 功能障碍的机制尚不清楚。

材料和方法

采用实时定量聚合酶链反应检测 Circ_0020397、miR-502-5p 和 Gremlin 1(GREM1)的表达。采用 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴盐(MTT)法分析细胞活力。采用 Western blot 法测定增殖细胞核抗原(PCNA)和 GREM1 的蛋白水平。通过双荧光素酶报告、RNA 下拉和 RNA 免疫沉淀实验证实 miR-502-5p 与 Circ_0020397 或 GREM1 的相互作用。

主要发现

IA 患者分离的 VSMCs 中 Circ_0020397 或 GREM1 表达下调,过表达 Circ_0020397 或 GREM1 促进 VSMC 活力并上调 PCNA 表达水平,而抑制它们则产生相反的效果。证实 miR-502-5p 可直接与 Circ_0020397 或 GREM1 结合,miR-502-5p 逆转 Circ_0020397 对 VSMC 活力和 PCNA 水平的影响。此外,miR-502-5p 过表达抑制 VSMC 活力并降低 PCNA 水平,而 GREM1 上调则减弱了这些作用。重要的是,Circ_0020397 可通过 miR-502-5p 在 VSMCs 中调节 GREM1 的表达。

意义

Circ_0020397 通过 miR-502-5p/GREM1 轴促进 VSMC 活力,在 IA 中的表型调节中发挥重要作用,为 IA 发病机制提供了新的见解,并为 IA 分子治疗提供了新的靶点。

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