17&bgr;-Estradiol Enhances Vascular Endothelial Ets-1/miR-126-3p Expression: The Possible Mechanism for Attenuation of Atherosclerosis

Ping Li, Jinzhi Wei, Xiaosa Li, Yang Cheng, Weiyu Chen, Yuhong Cui, T. Simoncini, Zhengtian Gu, Jun Yang, Xiaodong Fu
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引用次数: 38

Abstract

Context: Endothelial microRNA 126 (miR-126) attenuates the development of atherosclerosis (AS). However, there is no evidence showing the role of miR-126 in estrogen’s antiatherogenic effects. Objective: We hypothesized that 17&bgr;-estradiol (E2) modulates miR-126 expression and thus may improve endothelial function and retard AS development. Design/Setting/Participants: This was a prospective cohort study of 12 healthy regularly menstruating female volunteers. ApoE−/− mice were used as the atherosclerosis model and human umbilical vascular endothelial cells (HUVECs) were cultured as the cell model. Main Outcome Measures: Serum hormones and miR-126-3p levels were measured up to 3 times for 1 cycle. Real-time polymerase chain reaction, histology for atherosclerotic lesions, immunofluorescence, luciferase assay, transfection experiments, cell proliferation, migration and tube formation assay, and western blot were performed. Results: Serum concentrations of miR-126-3p in cycling women were higher at the ovulatory and luteal phases than in the follicular phase, and they were positively correlated with E2 values. Administration of miR-126-3p mimics to ApoE−/− mice-attenuated atherogenesis, and antagomir-126-3p partially reversed the protective effect of E2 on atherogenesis. In HUVECs, E2 increased miR-126-3p expression via upregulation of Ets-1 (a transcription factor for miR-126). c-Src/Akt signaling was important for E2-mediated expression of Ets-1/miR-126. E2 decreased expression of miR-126-3p target Spred1 (a protein that inhibits mitogenic signaling). Overexpression of Spred1 partially blocked enhancement of endothelial cell proliferation, migration, and tube formation by E2. Additionally, E2 regulates miR-126-3p–mediated expression of vascular cell adhesion molecule-1 to inhibit monocyte adhesion into HUVECs. Conclusions: E2 protection against atherogenesis is possibly mediated by Ets-1/miR-126.
雌二醇增强血管内皮Ets-1/miR-126-3p表达:可能的动脉粥样硬化衰减机制
背景:内皮microRNA 126 (miR-126)可减缓动脉粥样硬化(AS)的发展。然而,没有证据表明miR-126在雌激素的抗动脉粥样硬化作用中的作用。目的:我们假设17&bgr;-estradiol (E2)调节miR-126的表达,从而可能改善内皮功能并延缓AS的发展。设计/环境/参与者:这是一项前瞻性队列研究,共有12名健康、月经规律的女性志愿者。以ApoE−/−小鼠作为动脉粥样硬化模型,培养人脐血管内皮细胞(HUVECs)作为细胞模型。主要观察指标:血清激素和miR-126-3p水平测定3次,每1个周期。实时聚合酶链反应、动脉粥样硬化病变组织学、免疫荧光、荧光素酶测定、转染实验、细胞增殖、迁移和成管实验、western blot。结果:月经周期妇女血清miR-126-3p浓度在排卵期和黄体期高于卵泡期,且与E2值呈正相关。miR-126-3p模拟物对ApoE−/−小鼠的作用减弱了动脉粥样硬化,而安塔戈米尔-126-3p部分逆转了E2对动脉粥样硬化的保护作用。在huvec中,E2通过上调Ets-1 (miR-126的转录因子)增加了miR-126-3p的表达。c-Src/Akt信号通路在e2介导的Ets-1/miR-126表达中起重要作用。E2降低miR-126-3p靶蛋白Spred1(一种抑制有丝分裂信号传导的蛋白)的表达。过度表达Spred1部分阻断E2对内皮细胞增殖、迁移和管形成的增强作用。此外,E2调节mir -126-3p介导的血管细胞粘附分子-1的表达,以抑制单核细胞粘附到HUVECs。结论:E2对动脉粥样硬化的保护可能是由Ets-1/miR-126介导的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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