Triazole RGD antagonist reverts TGFβ1-induced endothelial-to-mesenchymal transition in endothelial precursor cells

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• 作者：Francesca Bianchini ; Silvia Peppicelli…
• 关键词：αvβ3 integrin ; Endothelial Colony ; Forming Cells (ECPCs) ; Endothelial ; to ; Mesenchymal Transition (EMT) ; Fibrosis ; Transforming Growth Factorβ1 (TGFβ1)
• 刊名：Molecular and Cellular Biochemistry
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：424
• 期：1-2
• 页码：99-110
• 全文大小：3467KB
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biochemistry, general; Medical Biochemistry; Oncology; Cardiology;
• 出版者：Springer US
• ISSN：1573-4919
• 卷排序：424

文摘

Fibrosis is the dramatic consequence of a dysregulated reparative process in which activated fibroblasts (myofibroblasts) and Transforming Growth Factor β1 (TGFβ1) play a central role. When exposed to TGFβ1, fibroblast and epithelial cells differentiate in myofibroblasts; in addition, endothelial cells may undergo endothelial-to-mesenchymal transition (EndoMT) and actively participate to the progression of fibrosis. Recently, the role of αv integrins, which recognize the Arg-Gly-Asp (RGD) tripeptide, in the release and signal transduction activation of TGFβ1 became evident. In this study, we present a class of triazole-derived RGD antagonists that interact with αvβ3 integrin. Above different compounds, the RGD-2 specifically interferes with integrin-dependent TGFβ1 EndoMT in Endothelial Colony-Forming Cells (ECPCs) derived from circulating Endothelial Precursor Cells (ECPCs). The RGD-2 decreases the amount of membrane-associated TGFβ1, and reduces both ALK5/TGFβ1 type I receptor expression and Smad2 phosphorylation in ECPCs. We found that RGD-2 antagonist reverts EndoMT, reducing α-smooth muscle actin (α-SMA) and vimentin expression in differentiated ECPCs. Our results outline the critical role of integrin in fibrosis progression and account for the opportunity of using integrins as target for anti-fibrotic therapeutic treatment.