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Gestational diabetes mellitus impairs fetal endothelial cell functions through a mechanism involving microRNA-101 and histone methyltransferase enhancer of zester homolog-2 (Translational Sciences)

Floris, Ilaria and Descamps, Betty and Vardeu, Antonella and Mitić, Tijana and Posadino, Anna Maria and Shantikumar, Saran and Sala-Newby, Graciela and Capobianco, Giampiero and Mangialardi, Giuseppe and Howard, Lynsey and Dessole, Salvatore and Urrutia, Raul and Pintus, Gianfranco and Emanueli, Costanza (2015) Gestational diabetes mellitus impairs fetal endothelial cell functions through a mechanism involving microRNA-101 and histone methyltransferase enhancer of zester homolog-2 (Translational Sciences). Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 35 , p. 664-674. eISSN 1524-4636. Article.

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DOI: 10.1161/ATVBAHA.114.304730

Abstract

Objective: Gestational diabetes mellitus (GDM) produces fetal hyperglycemia with increased lifelong risks for the exposed offspring of cardiovascular and other diseases. Epigenetic mechanisms induce long-term gene expression changes in response to in utero environmental perturbations. Moreover, microRNAs (miRs) control the function of endothelial cells (ECs) under physiological and pathological conditions and can target the epigenetic machinery. We investigated the functional and expressional effect of GDM on human fetal ECs of the umbilical cord vein (HUVECs). We focused on miR-101 and 1 of its targets, enhancer of zester homolog-2 (EZH2), which trimethylates the lysine 27 of histone 3, thus repressing gene transcription. EZH2 exists as isoforms α and β.
Approach and Results: HUVECs were prepared from GDM or healthy pregnancies and tested in apoptosis, migration, and Matrigel assays. GDM-HUVECs demonstrated decreased functional capacities, increased miR-101 expression, and reduced EZH2- β and trimethylation of histone H3 on lysine 27 levels. MiR-101 inhibition increased EZH2 expression and improved GDM-HUVEC function. Healthy HUVECs were exposed to high or normal D-glucose concentration for 48 hours and then tested for miR-101 and EZH2 expression. Similar to GDM, high glucose increased miR-101 expression. Chromatin immunoprecipitation using an antibody for EZH2 followed by polymerase chain reaction analyses for miR-101 gene promoter regions showed that both GDM and high glucose concentration reduced EZH2 binding to the miR-101 locus in HUVECs. Moreover, EZH2-β overexpression inhibited miR-101 promoter activity in HUVECs.
Conclusions: GDM impairs HUVEC function via miR-101 upregulation. EZH2 is both a transcriptional inhibitor and a target gene of miR-101 in HUVECs, and it contributes to some of the miR-101-induced defects of GDM-HUVECs.

Item Type:Article
ID Code:10947
Status:Published
Refereed:Yes
Uncontrolled Keywords:Gestational diabetes, endothelial cells, epigenomics, EZH2 protein human, microRNAs, polycomb repressive complex 2
Subjects:Area 06 - Scienze mediche > MED/40 Ginecologia e ostetricia
Area 05 - Scienze biologiche > BIO/10 Biochimica
Divisions:001 Università di Sassari > 01-a Nuovi Dipartimenti dal 2012 > Scienze Chirurgiche, Microchirurgiche e Mediche
001 Università di Sassari > 01-a Nuovi Dipartimenti dal 2012 > Scienze Biomediche
Publisher:Lippincott Williams & Wilkins
eISSN:1524-4636
Deposited On:10 Jun 2015 17:02

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