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        生物資訊

        CellSignal:TGF-β2對小鼠心臟內皮細胞的分子作用

        作者:admin 來源:本站 發布時間: 2017-02-26 12:56  瀏覽次數:
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         成纖維細胞是產生大部分組織中膠原蛋白和其他細胞外基質(ECM)蛋白的主要細胞。在受傷的組織中,轉化生長因子-β(TGF-β)激活成纖維細胞或分化的肌纖維母細胞合成過多的ECM蛋白,在心臟、腎臟和其他器官纖維化的發病機制中發揮了舉足輕重的作用。

        CellSignal:TGF-β2對小鼠心臟內皮細胞的分子作用
        最近研究表明,成纖維樣細胞過內皮細胞間質轉型(EndMT)演變成內皮細胞通,促進心肌纖維化的發病。然而EndMT的分子機制卻知之甚少。近來發表在Cellular Signalling雜志上的一項研究探究了TGF-β2對小鼠心臟內皮細胞(MCECs)的EndMT的分子作用。
        心臟內皮細胞暴露于TGF-β2會發生形態學變化,主要表現為攝取乙?;兔芏戎鞍?AC-LDL)能力的缺乏,以及α-平滑肌肌動蛋白(α-SMA)染色呈陽性,這些都證明心臟內皮細胞發生了間質轉型。
        心臟內皮細胞用TGF-β受體(TbetaRI)激酶的小分子抑制劑SB431542處理能完全阻斷TGF-β2誘導EndMT,但MEK抑制劑PD98059不能。在EndMT成纖維細胞樣細胞中,α-SMA,Snail,beta-catenin以及乙酰轉移酶P300(ATp300)的轉錄和蛋白水平明顯升高。
        重要的是,小分子RNA(miRNA)的相關數據顯示,在不同的心血管疾病失調的特定的miRNA在EndMT過稱中表達水平發生了改變。細胞P53蛋白表達水平,miR-125B的調控靶蛋白在EndMT源性的成纖維細胞樣細胞中下調。
        該研究首次報告了心臟endMT過程中差異表達的miRNA。這些結果共同表明,TbetaRI絲氨酸-蘇氨酸激酶誘導TGF-β信號和小分子RNA在轉錄后水平參與EndMT,促進EndMT源性的成纖維樣細胞纖維化信號。研究人員表示針對特定miRNA的藥物或許能逆轉心臟的EndMT,可能有助于預防和治療心肌纖維化。

        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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