miR-145 attenuates cardiac fibrosis through the AKT/GSK-3β/β-catenin signaling pathway by directly targeting SOX9 in fibroblasts.,Journal of Cellular Biochemistry

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miR-145 attenuates cardiac fibrosis through the AKT/GSK-3β/β-catenin signaling pathway by directly targeting SOX9 in fibroblasts.
Journal of Cellular Biochemistry ( IF 3.0 ) Pub Date : 2020-09-05 , DOI: 10.1002/jcb.29843
Shengyu Cui _{1,

2,

3} , Zhebo Liu _{1,

2,

3} , Bo Tao _{1,

2,

3} , Suzhen Fan _{1,

2,

3} , Yong Pu ₄ , Xiangping Meng ₅ , Dongqing Li ₆ , Hao Xia _{1,

2,

3} , Lin Xu _{1,

2,

3}

Affiliation

Myocardial infarction (MI) will inevitably result in cardiac fibrosis. In this study, we investigated the effect of microRNA‐145 (miR‐145) and transcription factor sex‐determining region Y box 9 (SOX9) in the production of cardiac fibrosis induced by MI. MI rat models were established by left anterior descending coronary artery (LAD) occlusion. Four weeks after LAD, the cardiac fibrosis level was assessed by Masson's trichrome staining. Cardiac fibroblasts (CFs) exposed to hypoxia were used to simulate MI‐induced fibrosis. Flow cytometry, cell counting kit‐8, and transwell assays were used to examine changes in CF apoptosis, proliferation, and migration, respectively. miR‐145 expression was measured by quantitative real‐time polymerase chain reaction. Immunofluorescence and Western blot analysis were performed to determine the relative expression of proteins. In comparison to the sham‐operated group, the expression of miR‐145 was significantly downregulated in the infarction peripheral area, whereas, SOX9 was upregulated. In the infarcted heart, the overexpression of miR‐145 significantly ameliorated cardiac fibrosis and cardiac function, and there was a negative correlation between miR‐145 and SOX9 expressions in hypoxic CFs in vitro. In addition, SOX9 was verified to be a functional target of miR‐145. Overexpression of miR‐145 or inhibition of SOX9 decreased CF proliferation, migration, and fibrosis, but augmented their apoptotic rate. Moreover, the upregulation of miR‐145 or suppression of SOX9 inhibited AKT and β‐catenin signaling in hypoxic CFs. Taken together, this study highlights a potential treatment for cardiac fibrosis through the targeted regulation of SOX9 by miR‐145, and our findings indicate that miR‐145 exerts anti‐fibrotic effects in MI via the negative regulation of SOX9 and its downstream AKT/GSK‐3β/β‐catenin pathways.

中文翻译：

miR-145 通过直接靶向成纤维细胞中的 SOX9，通过 AKT/GSK-3β/β-catenin 信号通路减弱心脏纤维化。

心肌梗塞（MI）不可避免地会导致心脏纤维化。在这项研究中，我们研究了 microRNA-145 (miR-145) 和转录因子性别决定区 Y 框 9 (SOX9) 在 MI 诱导的心脏纤维化产生中的作用。通过左冠状动脉前降支（LAD）闭塞建立MI大鼠模型。LAD 后 4 周，通过 Masson 三色染色评估心脏纤维化水平。暴露于缺氧的心脏成纤维细胞 (CFs) 用于模拟 MI 诱导的纤维化。流式细胞术、细胞计数试剂盒 8 和 transwell 测定分别用于检查 CF 细胞凋亡、增殖和迁移的变化。通过定量实时聚合酶链反应测量 miR-145 的表达。进行免疫荧光和蛋白质印迹分析以确定蛋白质的相对表达。与假手术组相比，miR-145在梗死外周区的表达显着下调，而SOX9的表达上调。在梗死心脏中，miR-145的过表达显着改善了心脏纤维化和心脏功能，体外缺氧CFs中miR-145和SOX9表达呈负相关。此外，SOX9 被证实是 miR-145 的功能靶点。miR-145 的过表达或 SOX9 的抑制降低了 CF 增殖、迁移和纤维化，但增加了它们的凋亡率。此外，miR-145 的上调或 SOX9 的抑制抑制了缺氧 CF 中的 AKT 和 β-catenin 信号传导。综合起来，

更新日期：2020-09-05

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