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CellSignal:TGF-β2对小鼠心脏内皮细胞的分子作用

作者:admin 来源:本站 发布时间: 2017-02-26 12:56  浏览次数:
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 成纤维细胞是产生大部分组织中胶原蛋白和其他细胞外基质(ECM)蛋白的主要细胞。在受伤的组织中,转化生长因子-β(TGF-β)激活成纤维细胞或分化的肌纤维母细胞合成过多的ECM蛋白,在心脏、肾脏和其他器官纤维化的发病机制中发挥了举足轻重的作用。

CellSignal:TGF-β2对小鼠心脏内皮细胞的分子作用
最近研究表明,成纤维样细胞过内皮细胞间质转型(EndMT)演变成内皮细胞通,促进心肌纤维化的发病。然而EndMT的分子机制却知之甚少。近来发表在Cellular Signalling杂志上的一项研究探究了TGF-β2对小鼠心脏内皮细胞(MCECs)的EndMT的分子作用。
心脏内皮细胞暴露于TGF-β2会发生形态学变化,主要表现为摄取乙酰化低密度脂蛋白(AC-LDL)能力的缺乏,以及α-平滑肌肌动蛋白(α-SMA)染色呈阳性,这些都证明心脏内皮细胞发生了间质转型。
心脏内皮细胞用TGF-β受体(TbetaRI)激酶的小分子抑制剂SB431542处理能完全阻断TGF-β2诱导EndMT,但MEK抑制剂PD98059不能。在EndMT成纤维细胞样细胞中,α-SMA,Snail,beta-catenin以及乙酰转移酶P300(ATp300)的转录和蛋白水平明显升高。
重要的是,小分子RNA(miRNA)的相关数据显示,在不同的心血管疾病失调的特定的miRNA在EndMT过称中表达水平发生了改变。细胞P53蛋白表达水平,miR-125B的调控靶蛋白在EndMT源性的成纤维细胞样细胞中下调。
该研究首次报告了心脏endMT过程中差异表达的miRNA。这些结果共同表明,TbetaRI丝氨酸-苏氨酸激酶诱导TGF-β信号和小分子RNA在转录后水平参与EndMT,促进EndMT源性的成纤维样细胞纤维化信号。研究人员表示针对特定miRNA的药物或许能逆转心脏的EndMT,可能有助于预防和治疗心肌纤维化。

原文摘要:

 

Fibroblasts are responsible for producing the majority of collagen and other extracellular matrix (ECM) proteins in tissues. In the injured tissue, transforming growth factor-β (TGF-β)-activated fibroblasts or differentiated myofibroblasts synthesize excessive ECM proteins and play a pivotal role in the pathogenesis of fibrosis in heart, kidney and other organs. Recent studies suggest that fibroblast-like cells, derived from endothelial cells by endothelial-to-mesenchymal transition (EndMT), contribute to the pathogenesis of cardiac fibrosis. The molecular basis of EndMT, however, is poorly understood. Here, we investigated the molecular basis of EndMT in mouse cardiac endothelial cells (MCECs) in response to TGF-β2. MCECs exposed to TGF-β2 underwent EndMT as evidenced by morphologic changes, lack of acetylated-low density lipoprotein (Ac-LDL) uptake, and the presence of alpha-smooth muscle actin (α-SMA) staining. Treatment with SB431542, a small molecule inhibitor of TGF-β-receptor I (TβRI) kinase, but not PD98059, a MEK inhibitor, completely blocked TGF-β2-induced EndMT. The transcript and protein levels of α-SMA, Snail and β-catenin as well as acetyltransferase p300 (ATp300) were elevated in EndMT derived fibroblast-like cells. Importantly, microRNA (miRNA) array data revealed that the expression levels of specific miRNAs, known to be dysregulated in different cardiovascular diseases, were altered during EndMT. The protein level of cellular p53, a bonafide target of miR-125b, was downregulated in EndMT-derived fibroblast-like cells. Here, we report for the first time, the differential expression of miRNAs during cardiac EndMT. These results collectively suggest that TβRI serine-threonine kinase-induced TGF-β signaling and microRNAs, the epigenetic regulator of gene expression at the posttranscriptional level, are involved in EndMT and promote profibrotic signaling in EndMT-derived fibroblast-like cells. Pharmacologic agents that restrict the progression of cardiac EndMT, a phenomenon that is found in adults only in the pathological conditions, in targeting specific miRNA may be helpful in preventing and treating cardiac fibrosis.
 

 

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