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CellSignal：TGF-β2對小鼠心臟內(nèi)皮細(xì)胞的分子作用

作者：admin 來源：本站發(fā)布時間： 2017-02-26 12:56　瀏覽次數(shù)：

購買進口儀器、試劑和耗材——就在始于2001年的畢特博生物 www.pyjb.com.cn

成纖維細(xì)胞是產(chǎn)生大部分組織中膠原蛋白和其他細(xì)胞外基質(zhì)(ECM)蛋白的主要細(xì)胞。在受傷的組織中，轉(zhuǎn)化生長因子-β(TGF-β)激活成纖維細(xì)胞或分化的肌纖維母細(xì)胞合成過多的ECM蛋白，在心臟、腎臟和其他器官纖維化的發(fā)病機制中發(fā)揮了舉足輕重的作用。

CellSignal：TGF-β2對小鼠心臟內(nèi)皮細(xì)胞的分子作用

最近研究表明，成纖維樣細(xì)胞過內(nèi)皮細(xì)胞間質(zhì)轉(zhuǎn)型(EndMT)演變成內(nèi)皮細(xì)胞通，促進心肌纖維化的發(fā)病。然而EndMT的分子機制卻知之甚少。近來發(fā)表在Cellular Signalling雜志上的一項研究探究了TGF-β2對小鼠心臟內(nèi)皮細(xì)胞(MCECs)的EndMT的分子作用。

心臟內(nèi)皮細(xì)胞暴露于TGF-β2會發(fā)生形態(tài)學(xué)變化，主要表現(xiàn)為攝取乙酰化低密度脂蛋白(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(nèi)皮細(xì)胞發(fā)生了間質(zhì)轉(zhuǎn)型。

心臟內(nèi)皮細(xì)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(dǎo)EndMT，但MEK抑制劑PD98059不能。在EndMT成纖維細(xì)胞樣細(xì)胞中，α-SMA，Snail，beta-catenin以及乙酰轉(zhuǎn)移酶P300(ATp300)的轉(zhuǎn)錄和蛋白水平明顯升高。

重要的是，小分子RNA(miRNA)的相關(guān)數(shù)據(jù)顯示，在不同的心血管疾病失調(diào)的特定的miRNA在EndMT過稱中表達(dá)水平發(fā)生了改變。細(xì)胞P53蛋白表達(dá)水平，miR-125B的調(diào)控靶蛋白在EndMT源性的成纖維細(xì)胞樣細(xì)胞中下調(diào)。

該研究首次報告了心臟endMT過程中差異表達(dá)的miRNA。這些結(jié)果共同表明，TbetaRI絲氨酸-蘇氨酸激酶誘導(dǎo)TGF-β信號和小分子RNA在轉(zhuǎn)錄后水平參與EndMT，促進EndMT源性的成纖維樣細(xì)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(zhuǎn)心臟的EndMT，可能有助于預(yù)防和治療心肌纖維化。

原文摘要：

Molecular basis of cardiac endothelial-to-mesenchymal transition (EndMT): differentialexpression of microRNAs during EndMT.

Ghosh AK, Nagpal V, Covington JW, Michaels MA, Vaughan DE.

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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