Objective

MicroRNAs (miRNAs) targeting has been revealed to be an appealing strategy for the treatment and management of atrial fibrillation (AF). In this research, we aimed to explore the mechanisms of miR-205-5p in reducing the high-fat diet (HFD)-induced atrial fibrosis through the EHMT2/IGFBP3 axis.

Methods

Expression levels of miR-205-5p, IGFBP3 and EHMT2 were determined in AF patients, cell fibrosis models and mouse atrial fibrosis models. Luciferase activity and RIP assays were performed to detect the binding between miR-205-5p and EHMT2, and ChIP assays were implemented to detect the enrichment of H3K9me2 and H3K4me3 in the promoter region of IGFBP3 in cells. The related experiments focusing on the inflammatory response, atrial fibrosis, mitochondrial damage, and metabolic abnormalities were performed to figure out the roles of miR-205-5p, IGFBP3, and EHMT2 in cell and mouse atrial fibrosis models.

Results

Low expression levels of miR-205-5p and IGFBP3 and a high expression of EHMT2 were found in AF patients, cell fibrosis models and mouse atrial fibrosis models. Upregulation of miR-205-5p reduced the expression of TGF-β1, α-SMA, Col III and other fibrosis-related proteins. miR-205-5p overexpression targeted EHMT2 to regulate the methylation of H3 histones to promote IGFBP3 expression, which in turn affected the fibrosis of atrial muscle cells. In HFD-induced atrial fibrosis mice, upregulated miR-205-5p or elevated IGFBP3 alleviated atrial fibrosis, mitochondrial damage, and metabolic abnormalities.

Conclusion

This study suggests that miR-205-5p attenuates HFD-induced atrial fibrosis via modulating the EHMT2/IGFBP3 axis.

Graphical Abstract

miR-205-5p alleviates high-fat diet-induced atrial fibrosis in mice via EHMT2/IGFBP3.

中文翻译：

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MicroRNA-205-5p 通过调节 EHMT2/IGFBP3 轴在高脂饮食诱导的心房纤维化中发挥抑制作用

客观的

MicroRNAs (miRNAs) 靶向已被证明是治疗和管理心房颤动 (AF) 的一种有吸引力的策略。在本研究中，我们旨在探索 miR-205-5p 通过 EHMT2/IGFBP3 轴减少高脂饮食 (HFD) 诱导的心房纤维化的机制。

方法

在 AF 患者、细胞纤维化模型和小鼠心房纤维化模型中测定 miR-205-5p、IGFBP3 和 EHMT2 的表达水平。进行荧光素酶活性和 RIP 测定以检测 miR-205-5p 和 EHMT2 之间的结合，并实施 ChIP 测定以检测 H3K9me2 和 H3K4me3 在细胞中 IGFBP3 启动子区域的富集。围绕炎症反应、心房纤维化、线粒体损伤和代谢异常进行了相关实验，以了解 miR-205-5p、IGFBP3 和 EHMT2 在细胞和小鼠心房纤维化模型中的作用。

结果

在 AF 患者、细胞纤维化模型和小鼠心房纤维化模型中发现 miR-205-5p 和 IGFBP3 的低表达水平和 EHMT2 的高表达水平。miR-205-5p 的上调降低了 TGF-β1、α-SMA、Col III 和其他纤维化相关蛋白的表达。miR-205-5p 过表达靶向 EHMT2 以调节 H3 组蛋白的甲基化以促进 IGFBP3 的表达，进而影响心房肌细胞的纤维化。在 HFD 诱导的心房纤维化小鼠中，上调 miR-205-5p 或升高的 IGFBP3 可减轻心房纤维化、线粒体损伤和代谢异常。

结论

该研究表明 miR-205-5p 通过调节 EHMT2/IGFBP3 轴来减轻 HFD 诱导的心房纤维化。

图形概要

miR-205-5p 通过 EHMT2/IGFBP3 减轻高脂饮食诱导的小鼠心房纤维化。