Liraglutide inhibits AngII-induced cardiac fibroblast proliferation and ECM deposition through regulating miR-21/PTEN/PI3K pathway,Cell and Tissue Banking

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Liraglutide inhibits AngII-induced cardiac fibroblast proliferation and ECM deposition through regulating miR-21/PTEN/PI3K pathway
Cell and Tissue Banking ( IF 1.4 ) Pub Date : 2022-07-06 , DOI: 10.1007/s10561-022-10021-9
Jun Wang ₁ , Run Guo ₁ , Xiaoli Ma ₁ , Ying Wang ₂ , Qianyu Zhang ₁ , Nan Zheng ₁ , Jun Zhang ₁ , Chenchen Li ₃

Affiliation

Background

Cardiac fibrosis characterized with the aberrant proliferation of cardiac fibroblasts and extracellular matrix (ECM) deposition is a major pathophysiological feature of atrial fibrillation (AF). Liraglutide has exerted an alleviative role in various cardiovascular diseases, and can also regulate the level of microRNAs (miRNAs). It has been reported that miR-21 modulated cardiac fibrosis in AF. However, the regulative effect of liraglutide on atrial fibrosis via miR-21 and the underlying mechanism are still unclear.

Methods

The atrial fibroblasts were isolated from the heart of C57BL/6 mice, and treated with Angiotensin II (AngII) and liraglutide. The proliferation, migration, and ECM deposition were determined by cell counting Kit-8 (CCK-8), Brdu, transwell assay, cell scratch, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blot and immunofluorescence. The underlying mechanism was explored after transfection of miR-21 mimics into cells.

Results

Liraglutide inhibited proliferation, migration, invasion of fibroblast cell and ECM deposition in AngII-stimulated cardiac fibroblasts. Additionally, liraglutide decreased the AngII-induced increase in the expression level of miR-21, but enhanced the expression of phosphatase and tensin homolog (PTEN), a target of miR-21, thereby suppressing the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway. Rescue assay confirmed that overexpression of miR-21 counteracted the ameliorative effect of liraglutide on the proliferation, migration, invasion and ECM deposition in fibroblasts stimulated by AngII.

Conclusions

Liraglutide dampened AngII-induced proliferation and migration, and ECM deposition of cardiac fibroblast via modulating miR-21/PTEN/PI3K pathway.

中文翻译：

利拉鲁肽通过调控miR-21/PTEN/PI3K通路抑制AngII诱导的心肌成纤维细胞增殖和ECM沉积

背景

以心脏成纤维细胞异常增殖和细胞外基质（ECM）沉积为特征的心脏纤维化是心房颤动（AF）的主要病理生理特征。利拉鲁肽对多种心血管疾病均有缓解作用，还可调节微小RNA（miRNA）水平。据报道，miR-21 调节 AF 中的心脏纤维化。然而，利拉鲁肽通过miR-21对心房纤维化的调节作用及其机制尚不清楚。

方法

从 C57BL/6 小鼠的心脏中分离出心房成纤维细胞，并用血管紧张素 II (AngII) 和利拉鲁肽处理。通过细胞计数 Kit-8 (CCK-8)、Brdu、transwell 测定、细胞划痕、逆转录-定量聚合酶链反应 (RT-qPCR)、蛋白质印迹和免疫荧光测定增殖、迁移和 ECM 沉积。在将 miR-21 模拟物转染到细胞中后探索了潜在的机制。

结果

利拉鲁肽抑制 AngII 刺激的心脏成纤维细胞中成纤维细胞的增殖、迁移、侵袭和 ECM 沉积。此外，利拉鲁肽降低了 AngII 诱导的 miR-21 表达水平的增加，但增强了磷酸酶和张力蛋白同源物 (PTEN) 的表达，后者是 miR-21 的靶标，从而抑制磷酸肌醇 3-激酶 (PI3K)/AKT信号通路。救援试验证实，miR-21 的过表达抵消了利拉鲁肽对 AngII 刺激的成纤维细胞增殖、迁移、侵袭和 ECM 沉积的改善作用。