miRNA-200c-3p promotes endothelial to mesenchymal transition and neointimal hyperplasia in artery bypass grafts.
miRNA-200c-3p promotes endothelial to mesenchymal transition and neointimal hyperplasia in artery bypass grafts.
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miRNA-200c-3p 促进动脉搭桥术中内皮向间质转化和新内膜增生
DOI：
10.1002/path.5574
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Xiao Q
中科院分区：
文献类型：
--
作者：
Chen D;Zhang C;Chen J;Yang M;Afzal TA;An W;Maguire EM;He S;Luo J;Wang X;Zhao Y;Wu Q;Xiao Q
越来越多的证据表明，内皮-间充质转化（EndoMT）在各种病理条件下发挥着关键作用。microRNA-200 c-3 p（miR-200 c-3 p）与上皮细胞向间充质细胞转化有关。然而，miR-200 c-3 p在动脉旁路移植物中的EndoMT和新生内膜增生中的功能作用仍然很大程度上未知。在这里，我们证明了miR-200 c-3 p在EndoMT中的关键作用。蛋白质组学和荧光素酶活性测定显示，Fermitin家族成员2（FERM 2）是miR-200 c-3 p在EndoMT过程中的功能靶标。FERMT 2基因失活重现了miR-200 c-3 p过表达对EndoMT的影响，并且miR-200 c-3 p抑制对EndoMT的抑制作用被FERMT 2敲低逆转。进一步的机制研究表明，FERM 2通过阻止血清反应因子核转位和通过与Y-box结合蛋白1相互作用阻止内皮mRNA衰变来抑制平滑肌基因表达。在使用内皮谱系示踪的主动脉移植模型中，我们观察到miR-200 c-3 p表达显著上调，并且EndoMT有助于移植动脉中的新生内膜增生。移植动脉中的MiR-200 c-3 p抑制显著上调FERM 2基因表达，从而阻止EndoMT并减少新生内膜形成。重要的是，我们发现在患有动脉粥样硬化病变的人股动脉中存在高水平的EndoMT，并且miR-200 c-3 p表达显著增加，而FERMT 2表达水平在患病的人动脉中显著降低。总的来说，我们已经记录了miR-200 c-3 p在移植动脉中的EndoMT和新生内膜增生中的意外作用。我们的发现为通过特异性靶向miR-200 c-3 p/FERM 2调节轴治疗血管疾病提供了新的治疗机会。版权所有2020作者。病理学杂志由John Wiley & Sons，Ltd.代表大不列颠和爱尔兰病理学会出版。
Increasing evidence has suggested a critical role for endothelial‐to‐mesenchymal transition (EndoMT) in a variety of pathological conditions. MicroRNA‐200c‐3p (miR‐200c‐3p) has been implicated in epithelial‐to‐mesenchymal transition. However, the functional role of miR‐200c‐3p in EndoMT and neointimal hyperplasia in artery bypass grafts remains largely unknown. Here we demonstrated a critical role for miR‐200c‐3p in EndoMT. Proteomics and luciferase activity assays revealed that fermitin family member 2 (FERM2) is the functional target of miR‐200c‐3p during EndoMT. FERMT2 gene inactivation recapitulates the effect of miR‐200c‐3p overexpression on EndoMT, and the inhibitory effect of miR‐200c‐3p inhibition on EndoMT was reversed by FERMT2 knockdown. Further mechanistic studies revealed that FERM2 suppresses smooth muscle gene expression by preventing serum response factor nuclear translocation and preventing endothelial mRNA decay by interacting with Y‐box binding protein 1. In a model of aortic grafting using endothelial lineage tracing, we observed that miR‐200c‐3p expression was dramatically up‐regulated, and that EndoMT contributed to neointimal hyperplasia in grafted arteries. MiR‐200c‐3p inhibition in grafted arteries significantly up‐regulated FERM2 gene expression, thereby preventing EndoMT and reducing neointimal formation. Importantly, we found a high level of EndoMT in human femoral arteries with atherosclerotic lesions, and that miR‐200c‐3p expression was significantly increased, while FERMT2 expression levels were dramatically decreased in diseased human arteries. Collectively, we have documented an unexpected role for miR‐200c‐3p in EndoMT and neointimal hyperplasia in grafted arteries. Our findings offer a novel therapeutic opportunity for treating vascular diseases by specifically targeting the miR‐200c‐3p/FERM2 regulatory axis. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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影响因子：
8.8
作者：
Chen PY;Qin L;Barnes C;Charisse K;Yi T;Zhang X;Ali R;Medina PP;Yu J;Slack FJ;Anderson DG;Kotelianski V;Wang F;Tellides G;Simons M
通讯作者：
Simons M
影响因子：
7.7
作者：
Frye, Bjoern C.;Halfter, Sarah;Djudjaj, Sonja;Muehlenberg, Philipp;Weber, Susanne;Raffetseder, Ute;En-Nia, Abdelaziz;Knott, Hanna;Baron, Jens M.;Dooley, Steven;Bernhagen, Juergen;Mertens, Peter R.
通讯作者：
Mertens, Peter R.
DOI：
10.1083/jcb.201701176
发表时间：
2017-11-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Böttcher RT;Veelders M;Rombaut P;Faix J;Theodosiou M;Stradal TE;Rottner K;Zent R;Herzog F;Fässler R
通讯作者：
Fässler R
DOI：
10.1016/j.bbrc.2015.01.114
发表时间：
2015-03-06
影响因子：
3.1
作者：
Ha, Bin;Lee, Eun Byul;Jang, Ho Hee
通讯作者：
Jang, Ho Hee
影响因子：
8.7
作者：
Dietrich, H;Hu, YH;Xu, QB
通讯作者：
Xu, QB