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首页> 美国卫生研究院文献>International Journal of Clinical and Experimental Pathology >MicroRNA-142-3p inhibits high-glucose-induced endothelial-to-mesenchymal transition through targeting TGF-β1/Smad pathway in primary human aortic endothelial cells
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MicroRNA-142-3p inhibits high-glucose-induced endothelial-to-mesenchymal transition through targeting TGF-β1/Smad pathway in primary human aortic endothelial cells

机译：MicroRNA-142-3p通过靶向原代人主动脉内皮细胞中的TGF-β1/ Smad途径抑制高糖诱导的内皮向间充质转化

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Myocardial fibrosis is an important pathological feature of diabetic cardiomyopathy (DCM) and endothelial-to-mesenchymal transition (EndMT) is an essential process for myocardial fibrosis. Recent studies have demonstrated an association between miRs and DCM. Therefore, the aim of this study is to investigate the role and the mechanism of miRNAs in the process of EndMT. We simulated the conditions occurring in EndMT by application of high glucose in primary human aortic endothelial cells (HAECs). Firstly, we compared the expression profiles of miRNAs in HAECs with or without HG treatment using microarray. Then, after addition of miR-142-3p mimics, the expression levels of EndMT markers were assessed by qRT-PCR and Western Blot. Moreover, bioinformatics analysis and luciferase assay were used to confirm the direct regulation of miR-142-3p to TGF-β1. Furthermore, the role of TGF-β1 in the inhibitory effect of miR-142-3p on EndMT was evaluated. In addition, the expressions of TGF-β1/Smad signaling signatures were measured by Western Blot. MiR-142-3p screened by miRNA microarray was significantly down-regulated in HAECs under HG stimulation in a dose and time dependent manner. Subsequently, we found that overexpression of miR-142-3p could inhibit HG-induced EndMT, as evidenced by decreased α-SMA and vimentin expression, and increased CD31 and VE-cadherin expression. Of note, transforming growth factor beta 1 (TGF-β1), one of the molecular mediators implicated in the progression of EndMT, was confirmed to be downstream target gene of miR-142-3p in HAECs. Moreover, TGF-β1 overexpression remarkably abolished the inhibitory effects of miR-142-3p overexpression on HG induced EndMT. Finally, miR-142-3p also mediated its anti-EndMT action by inactivation of TGF-β1/Smad pathway, as demonstrated by downregulation of TGF-β1, phospho-Smad2 and phospho-Smad2. Our findings demonstrated that miR-142-3p could attenuate HG-induced EndMT in HAECs, the mechanism of which may be at least partly through blocking TGF-β1/Smad signaling pathway. This might provide a potential therapeutic target for DCM in future.
机译：心肌纤维化是糖尿病性心肌病（DCM）的重要病理特征，内皮-间充质转化（EndMT）是心肌纤维化的重要过程。最近的研究表明，miR和DCM之间存在关联。因此，本研究的目的是研究miRNA在EndMT过程中的作用和机制。我们通过在原代人主动脉内皮细胞（HAEC）中应用高葡萄糖来模拟EndMT中发生的情况。首先，我们比较了使用微阵列在有或没有进行HG处理的HAEC中miRNA的表达谱。然后，在添加miR-142-3p模拟物后，通过qRT-PCR和Western Blot评估EndMT标志物的表达水平。此外，生物信息学分析和荧光素酶测定法被用于证实miR-142-3p对TGF-β1的直接调节。此外，评价了TGF-β1在miR-142-3p对EndMT的抑制作用中的作用。另外，通过Western印迹测量TGF-β1/ Smad信号转导签名的表达。通过miRNA芯片筛选的miR-142-3p在HG刺激下在HAEC中以剂量和时间依赖性方式显着下调。随后，我们发现miR-142-3p的过表达可以抑制HG诱导的EndMT，这可以通过降低α-SMA和波形蛋白的表达以及增加CD31和VE-钙粘蛋白的表达来证明。值得注意的是，转化生长因子β1（TGF-β1）是EndMT进展的分子介体之一，已被证实是HAECs中miR-142-3p的下游靶基因。此外，TGF-β1的过表达显着消除了miR-142-3p过表达对HG诱导的EndMT的抑制作用。最后，miR-142-3p还通过失活TGF-β1/ Smad途径来介导其抗EndMT作用，如TGF-β1，磷酸Smad2和磷酸Smad2的下调所证明的。我们的发现表明，miR-142-3p可以减弱HG诱导的HAECs EndMT，其机制可能至少部分是通过阻断TGF-β1/ Smad信号通路。这可能会在将来为DCM提供潜在的治疗目标。

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