The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China.
Department of Gerontology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital.
Int J Biol Sci. 2021 Oct 3;17(15):4122-4139. doi: 10.7150/ijbs.60302. eCollection 2021.
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). ApoE-/- mice were fed a high-fat diet and then injected with DKK1i or DKK1 lentivirus to study the effects of DKK1. , 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. 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. 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.
血管生成参与多种生物学过程，包括动脉粥样硬化（AS）和癌症。Dickkopf1（DKK1）在肿瘤和 AS 中都发挥着多种作用，并且已成为癌症进展和预后的潜在生物标志物。靶向 DKK1 是肿瘤治疗的一个不错选择。许多抗癌疗法都与特定的心血管毒性有关。然而，DKK1 中和治疗对 AS 的影响尚不清楚。我们专注于 DKK1 如何影响 AS 和氧化低密度脂蛋白（ox-LDL）诱导的人脐静脉内皮细胞（HUVEC）中的血管生成。载脂蛋白 E 基因敲除（ApoE-/-）小鼠喂食高脂肪饮食，然后注射 DKK1i 或 DKK1 慢病毒，以研究 DKK1 的作用。进行了启动子分析、蛋白质分析、数据库挖掘、双荧光素酶报告基因检测（DLR）、电泳迁移率变动分析（EMSA）、染色质免疫沉淀（ChIP）和共免疫沉淀（co-IP）实验，以研究 DKK1 生物发生的机制。进行了细胞迁移和血管生成实验，以研究 DKK1 的功能和调控机制。通过 DKK1 的敲低或过表达，DKK1 参与了 ApoE-/- 小鼠斑块中的血管生成，以及 ox-LDL 诱导的 HUVEC 中的血管生成。DKK1 通过 CKAP4/PI3K 通路诱导血管生成（增加迁移和毛细血管形成，诱导 VEGFR-2/VEGF-A/MMP 的表达），而不依赖于 Wnt/β-catenin。ox-LDL 增加了 Ets-1 和 c-jun 的表达和核转移，并在 HUVEC 中诱导 DKK1 的转录活性。Ets-1 与 c-jun 和 CBP 一起可以结合 DKK1 的启动子并增强 DKK1 的转录。miR33a-5p 在 ox-LDL 诱导的 HUVECs 和高脂肪饮食 ApoE-/- 小鼠的主动脉中表达下调。Ets-1 是 miR33a-5p 的直接靶标。miR33a-5p/Ets-1/ DKK1 轴参与了血管生成。miR33a-5p/Ets-1/ DKK1 信号通过 CKAP4/PI3K 通路参与 ox-LDL 诱导的 HUVEC 血管生成。这些新发现为肿瘤治疗和心血管保护提供了合理的依据和显著的方法。
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