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.
Topic: atherosclerosis polymerase chain reaction signal transduction western blotting cell proliferation endothelial cells estradiol adhesions apolipoprotein e endothelium fluorescent antibody technique menstrual cycle, proliferative phase luciferases monocytes vascular cell adhesion molecule-1 mice transcription factor atherogenesis protein overexpression proto-oncogene proteins c-akt micro rna spred-1 protein attenuation antagomirs
Issue Section: Clinical Research Article

Ping Li Jinzhi Wei Xiaosa Li Yang Cheng Weiyu Chen Yuhong Cui Tommaso Simoncini Zhengtian Gu Jun Yang Xiaodong Fu
(2017) 102 (2): 594-603. DOI: https://doi.org/10.1210/jc.2016-2974

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