Dickkopf-1 promotes Vascular Smooth Muscle Cell proliferation and migration through upregulating UHRF1 during Cyclic Stretch application.
Dickkopf-1 promotes Vascular Smooth Muscle Cell proliferation and migration through upregulating UHRF1 during Cyclic Stretch application.
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Dickkopf-1 在循环拉伸过程中通过上调 UHRF1 促进血管平滑肌细胞增殖和迁移
DOI：
10.7150/ijbs.56247
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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：
Zheng TF;Liu XL;Li X;Wang QQ;Zhao YC;Li X;Li MM;Zhang Y;Zhang M;Zhang WC;Zhang C;Zhang Y;Zhang M
Dickkopf-1 （DKK1）最近被证明在心血管疾病中发挥重要作用。这项工作的目的是评估DKK1在通过机械拉伸调节平滑肌细胞功能中的作用以及这一过程的潜在机制。方法：对野生型C57BL/6J小鼠进行假手术或腹主动脉缩窄（AAC）手术。免疫组化染色和Western blotting检测DKK1的表达水平。分析DKK1在血管平滑肌细胞（VSMC）增殖和迁移中的功能。转录组测序分析确定DKK1调控的差异表达基因和途径。使用平滑肌特异性Dkk1敲除小鼠来确认Dkk1在体内的功能。染色质免疫沉淀（ChIP）用于确认dna -蛋白相互作用。启动子荧光素酶分析用于检测转录因子活性。结果：我们发现AAC显著提高了体内胸主动脉和冠状动脉的DKK1蛋白水平。在体外，高水平拉伸（18%）诱导VSMCs中DKK1的表达。敲除DKK1抑制VSMC在高水平拉伸下的增殖和迁移（18%）。我们发现含有PHD和RING finger domains 1 （UHRF1）的泛素样蛋白是DKK1的靶基因。用小干扰rna敲低UHRF1部分逆转了重组DKK1对VSMCs的调节作用。VSMC中特异性缺失DKK1足以减弱aac诱导的UHRF1上调、动脉介质增厚和VSMC增殖增加。此外，我们发现DKK1通过YAP-TEAD途径调节UHRF1的表达。TEAD1和TEAD4直接结合到UHRF1的启动子上，阻断YAP-TEAD相互作用可抑制DKK1导致的UHRF1上调。结论：本研究揭示DKK1通过YAP-TEAD通路调节UHRF1表达，介导平滑肌细胞功能的机械拉伸调节。
Dickkopf-1 (DKK1) was recently shown to play an important role in cardiovascular disease. The aim of this work was to assess the role of DKK1 in the regulation of smooth muscle cell function by mechanical stretch and the mechanisms underlying this process. Methods: Wild-type C57BL/6J mice were subjected to sham or abdominal aortic constriction (AAC) surgery. The expression level of DKK1 was examined by immunohistochemical staining and Western blotting. Analyses of DKK1 function in vascular smooth muscle cell (VSMC) proliferation and migration were performed. Transcriptome sequencing analysis was performed to identify the differentially expressed genes and pathways regulated by DKK1. Smooth muscle-specific Dkk1 knockout mice were used to confirm the function of DKK1 in vivo. Chromatin immunoprecipitation (ChIP) was used to confirm DNA-protein interactions. Promoter luciferase analysis was used to detect transcription factor activity. Results: We found that AAC significantly increased DKK1 protein levels in the thoracic aorta and coronary artery in vivo. In vitro, high-level stretch (18%) induced the expression of DKK1 in VSMCs. Knocking down DKK1 inhibited VSMC proliferation and migration under high-level stretch (18%). We identified ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) as a target gene of DKK1. Knockdown of UHRF1 with small interfering RNAs partially reversed the regulatory effect of recombinant DKK1 on VSMCs. Specific deletion of DKK1 in VSMCs was sufficient to attenuate the AAC-induced upregulation of UHRF1, thickening of arterial media and increase in VSMC proliferation. Furthermore, we found that DKK1 regulated UHRF1 expression through the YAP-TEAD pathway. TEAD1 and TEAD4 bound directly to the promoter of UHRF1, and blocking the YAP-TEAD interaction inhibited UHRF1 upregulation due to DKK1. Conclusions: This study reveals that DKK1 mediates the mechanical stretch regulation of smooth muscle cell function by modulating UHRF1 expression through the YAP-TEAD pathway.
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发表时间：
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影响因子：
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