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

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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.

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