MiR-375 Inhibitor Alleviates Inflammation and Oxidative Stress by Upregulating the GPR39 Expression in Atherosclerosis

IF 1.2 4区 医学 Q3 CARDIAC & CARDIOVASCULAR SYSTEMS International heart journal Pub Date : 2024-01-31 DOI:10.1536/ihj.23-155
Hui Luo, Lin Zhao, Bo Dong, Yanghong Liu
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引用次数: 0

Abstract

Atherosclerosis may be caused or developed by an immune response and antioxidation imbalance. MicroRNA-375 (miR-375) or G-protein-coupled receptor 39 (GPR39) is involved in vascular endothelial cell injury, but their role in atherosclerosis is unknown. This experiment aimed to determine the action of the miR-375/GPR39 axis in atherosclerosis.

Human aortic endothelial cells (HAECs) were treated with 10 ng/mL of oxidised low-density lipoprotein (ox-LDL) for 24 hours to induce HAEC injury, which was treated by the miR-375 inhibitor, GPR39 inhibitor, or agonist. High-fat diet (HFD) -induced ApoE−/− mice were made as an atherosclerosis model for miR-375 inhibitor treatment. Cell Counting Kit-8 was applied to detect HAEC viability. HAEC apoptosis and ROS levels were measured using flow cytometry. Vascular histopathology and the GPR39 expression were detected using hematoxylin-eosin and immunohistochemistry. The expressions of interleukin (IL) -6, IL-1β, and tumour necrosis factor-α (TNF-α) were assessed using an enzyme-linked immunosorbent assay. The miR-375, GPR39, NOX-4, and p-IκBα/IκBα levels were measured using quantitative reverse transcription polymerase chain reaction or western blot.

MiR-375 and GPR39 levels increased and decreased in ox-LDL-treated HAECs, respectively. The miR-375 inhibitor or GPR39 agonist promoted cell viability and inhibited apoptosis in ox-LDL-induced HAEC injury. The miR-375 inhibitor also significantly downregulated the IL-6, IL-1β, TNF-α, p-IκBα/IκBα, ROS, and NOX-4 expressions to alleviate oxidative stress and inflammation, which were reversed by the GPR39 inhibitor. An in vivo experiment proved that the miR-375 inhibitor upregulated the GPR39 expression and improved inflammation, oxidative stress, and endothelial cell damage associated with atherosclerosis.

The miR-375 inhibitor improved inflammation, oxidative stress, and cell damage in ox-LDL-induced HAECs and HFD-induced ApoE−/− mice by promoting the GPR39 expression, which provided a new theoretical basis for the clinical treatment of atherosclerosis.

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MiR-375 抑制剂通过上调动脉粥样硬化中 GPR39 的表达缓解炎症和氧化应激
动脉粥样硬化可能是由免疫反应和抗氧化失衡引起或发展的。微RNA-375(miR-375)或G蛋白偶联受体39(GPR39)参与血管内皮细胞损伤,但它们在动脉粥样硬化中的作用尚不清楚。本实验旨在确定miR-375/GPR39轴在动脉粥样硬化中的作用。用10纳克/毫升氧化低密度脂蛋白(ox-LDL)处理人主动脉内皮细胞(HAECs)24小时,诱导HAEC损伤,用miR-375抑制剂、GPR39抑制剂或激动剂处理HAEC损伤。高脂饮食(HFD)诱导的载脂蛋白E-/-小鼠作为动脉粥样硬化模型,接受 miR-375 抑制剂治疗。应用细胞计数试剂盒 8 检测 HAEC 的存活率。使用流式细胞术检测 HAEC 的凋亡和 ROS 水平。使用苏木精-伊红和免疫组化检测血管组织病理学和 GPR39 的表达。白细胞介素(IL)-6、IL-1β和肿瘤坏死因子-α(TNF-α)的表达采用酶联免疫吸附试验进行评估。采用定量反转录聚合酶链反应或 Western 印迹法测定了 miR-375、GPR39、NOX-4 和 p-IκBα/IκBα 的水平。在氧化-LDL诱导的HAEC损伤中,miR-375抑制剂或GPR39激动剂促进了细胞活力并抑制了细胞凋亡。miR-375 抑制剂还能显著下调 IL-6、IL-1β、TNF-α、p-IκBα/IκBα、ROS 和 NOX-4 的表达,从而减轻氧化应激和炎症反应,而 GPR39 抑制剂则能逆转这些反应。体内实验证明,miR-375抑制剂上调了GPR39的表达,改善了动脉粥样硬化相关的炎症、氧化应激和内皮细胞损伤。miR-375抑制剂通过促进GPR39的表达,改善了ox-LDL诱导的HAECs和HFD诱导的载脂蛋白E-/-小鼠的炎症、氧化应激和细胞损伤,为动脉粥样硬化的临床治疗提供了新的理论依据。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
International heart journal
International heart journal 医学-心血管系统
CiteScore
2.50
自引率
6.70%
发文量
148
审稿时长
6-12 weeks
期刊介绍: Authors of research articles should disclose at the time of submission any financial arrangement they may have with a company whose product figures prominently in the submitted manuscript or with a company making a competing product. Such information will be held in confidence while the paper is under review and will not influence the editorial decision, but if the article is accepted for publication, the editors will usually discuss with the authors the manner in which such information is to be communicated to the reader.
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