17β-雌二醇增强血管内皮Ets-1/miR-126-3p表达：动脉粥样硬化减轻的可能机制

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

作者信息

Li Ping, Wei Jinzhi, Li Xiaosa, Cheng Yang, Chen Weiyu, Cui Yuhong, Simoncini Tommaso, Gu Zhengtian, Yang Jun, Fu Xiaodong

机构信息

Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, People's Republic of China.

Department of Gynecology and Obstetrics, Municipal First People's Hospital of Guangzhou, Guangzhou 510180, People's Republic of China.

出版信息

J Clin Endocrinol Metab. 2017 Feb 1;102(2):594-603. doi: 10.1210/jc.2016-2974.

DOI:10.1210/jc.2016-2974

PMID:27870587

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 17β-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.

摘要

背景

内皮细胞微小RNA 126（miR - 126）可减轻动脉粥样硬化（AS）的发展。然而，尚无证据表明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17β - 雌二醇（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/地点/参与者：这是一项对12名健康、月经规律的女性志愿者进行的前瞻性队列研究。载脂蛋白E基因敲除（ApoE - / -）小鼠用作动脉粥样硬化模型，人脐静脉血管内皮细胞（HUVECs）作为细胞模型进行培养。

主要观察指标

在1个周期内最多测量3次血清激素和miR - 126 - 3p水平。进行实时聚合酶链反应、动脉粥样硬化病变的组织学检查、免疫荧光、荧光素酶测定、转染实验、细胞增殖、迁移和管形成测定以及蛋白质印迹分析。

结果

月经周期女性血清中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。给ApoE - / -小鼠注射miR - 126 - 3p模拟物可减轻动脉粥样硬化的发生，而抗miR - 126 - 3p部分逆转了E2对动脉粥样硬化发生的保护作用。在HUVECs中，E2通过上调Ets - 1（miR - 126的转录因子）增加miR - 126 - 3p的表达。c - Src/Akt信号通路对E2介导的Ets - 1/miR - 126表达很重要。E2降低miR - 126 - 3p靶标Spred1（一种抑制促有丝分裂信号的蛋白质）的表达。Spred1的过表达部分阻断了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介导的血管细胞黏附分子 - 1的表达，以抑制单核细胞黏附到HUVECs中。