The pro-angiogenesis effect of miR33a-5p/Ets-1/DKK1 signaling in ox-LDL induced HUVECs.
The pro-angiogenesis effect of miR33a-5p/Ets-1/DKK1 signaling in ox-LDL induced HUVECs.
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miR33a-5p/Ets-1/DKK1 信号在 ox-LDL 诱导的 HUVEC 中的促血管生成作用
DOI：
10.7150/ijbs.60302
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发表时间：
2021
影响因子：
9.2
通讯作者：
Zhang M
中科院分区：
文献类型：
--
作者：
Di M;Zhang Y;Zeng R;Liu X;Chen W;Zhang M;Zhang C;Li M;Zhang M
目的：血管生成涉及多种生物过程，包括动脉粥样硬化（AS）和癌症。Dickkopf1 （DKK1）在肿瘤和AS中都起着许多作用，并已成为癌症进展和预后的潜在生物标志物。靶向DKK1是肿瘤治疗的良好选择。许多抗癌疗法与特定的心血管毒性有关。然而，DKK1中和疗法对AS的影响尚不清楚。我们重点研究了DKK1如何影响AS和ox- ldl诱导的人脐静脉内皮细胞（HUVECs）的血管生成。方法：采用高脂饲料喂养ApoE-/-小鼠，然后注射DKK1i或DKK1慢病毒，研究DKK1的作用。在体外，通过启动子分析、蛋白分析、数据库挖掘、双荧光素酶报告基因法（DLR）、电泳迁移量转移法（EMSA）、染色质免疫沉淀法（ChIP）和共免疫沉淀法（co-IP）研究DKK1的生物发生机制。通过细胞迁移和血管生成实验来研究DKK1的功能和调控机制。结果：DKK1通过敲低或过表达DKK1和ox- ldl诱导的HUVECs参与ApoE-/-小鼠斑块中的血管生成。DKK1通过CKAP4/PI3K途径诱导血管生成（增加迁移和毛细血管形成，诱导VEGFR-2/VEGF-A/MMP的表达），独立于Wnt/β-catenin。ox-LDL增加了Ets-1和c-jun的表达和核转移，诱导了HUVECs中DKK1的转录活性。Ets-1与c-jun和CBP可结合DKK1启动子，增强DKK1转录。MiR33a-5p在ox-LDL诱导的huvec和高脂饮食ApoE-/-小鼠主动脉中下调。Ets-1是miR33a-5p的直接靶点。MiR33a-5p/Ets-1/ DKK1轴参与血管生成。结论：MiR33a-5p/Ets-1/DKK1信号通过CKAP4/PI3K途径参与ox- ldl诱导的HUVECs血管生成。这些新发现为肿瘤治疗和心血管保护提供了理论依据和值得注意的方法。
Objective: Angiogenesis is involved in multiple biological processes, including atherosclerosis (AS) and cancer. Dickkopf1 (DKK1) plays many roles in both tumors and AS and has emerged as a potential biomarker of cancer progression and prognosis. Targeting DKK1 is a good choice for oncological treatments. Many anticancer therapies are associated with specific cardiovascular toxicity. However, the effects of DKK1 neutralizing therapy on AS are unclear. We focused on how DKK1 affected angiogenesis in AS and ox-LDL-induced human umbilical vein endothelial cells (HUVECs). Methods: ApoE-/- mice were fed a high-fat diet and then injected with DKK1i or DKK1 lentivirus to study the effects of DKK1. In vitro, promoter assays, protein analysis, database mining, dual-luciferase reporter assay (DLR), electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), and coimmunoprecipitation (co-IP) were used to study the mechanism of DKK1 biogenesis. Cell migration and angiogenesis assays were performed to investigate the function and regulatory mechanisms of DKK1. Results: DKK1 participated in angiogenesis both in the plaques of ApoE-/- mice by knockdown or overexpression of DKK1 and ox-LDL-induced HUVECs. DKK1 induced angiogenesis (increasing migration and capillary formation, inducing expression of VEGFR-2/VEGF-A/MMP) via the CKAP4/PI3K pathway, independent of Wnt/β-catenin. ox-LDL increased the expression and nuclear transfer of Ets-1 and c-jun, and induced the transcriptional activity of DKK1 in HUVECs. Ets-1, along with c-jun and CBP, could bind to the promoter of DKK1 and enhance DKK1 transcription. MiR33a-5p was downregulated in ox-LDL induced HUVECs and aortic artery of high-fat diet ApoE-/- mice. Ets-1 was a direct target of miR33a-5p. MiR33a-5p/Ets-1/ DKK1 axis contributed to angiogenesis. Conclusions: MiR33a-5p/Ets-1/DKK1 signaling participated in ox-LDL-induced angiogenesis of HUVECs via the CKAP4/PI3K pathway. These new findings provide a rationale and notable method for tumor therapy and cardiovascular protection.
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影响因子：
21.3
作者：
Hergenreider, Eduard;Heydt, Susanne;Dimmeler, Stefanie
通讯作者：
Dimmeler, Stefanie
影响因子：
7.3
作者：
Kagey MH;He X
通讯作者：
He X
DOI：
10.1016/j.cjca.2017.01.001
发表时间：
2017-03
期刊：
The Canadian journal of cardiology
影响因子：
--
作者：
Laffont B;Rayner KJ
通讯作者：
Rayner KJ
影响因子：
4.8
作者：
Kim, Hey-Yon;Park, Ji-Hye;Kong, Gu
通讯作者：
Kong, Gu
影响因子：
9.5
作者：
Ling, Shukuan;Birnbaum, Yochai;Ye, Yumei
通讯作者：
Ye, Yumei