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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.
- Source :
-
Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2015 Mar; Vol. 35 (3), pp. 664-74. Date of Electronic Publication: 2015 Jan 22. - Publication Year :
- 2015
-
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.<br />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.<br />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.<br /> (© 2015 American Heart Association, Inc.)
- Subjects :
- Apoptosis
Binding Sites
Case-Control Studies
Cell Movement
Cell Survival
Cells, Cultured
Diabetes, Gestational genetics
Diabetes, Gestational pathology
Diabetes, Gestational physiopathology
Enhancer of Zeste Homolog 2 Protein
Female
Gestational Age
Glucose metabolism
Histones metabolism
Human Umbilical Vein Endothelial Cells pathology
Humans
Methylation
Neovascularization, Physiologic
Phenotype
Polycomb Repressive Complex 2 genetics
Pregnancy
Promoter Regions, Genetic
RNA Interference
Signal Transduction
Time Factors
Transcription, Genetic
Transfection
Up-Regulation
Diabetes, Gestational enzymology
Human Umbilical Vein Endothelial Cells enzymology
MicroRNAs metabolism
Polycomb Repressive Complex 2 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4636
- Volume :
- 35
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Arteriosclerosis, thrombosis, and vascular biology
- Publication Type :
- Academic Journal
- Accession number :
- 25614281
- Full Text :
- https://doi.org/10.1161/ATVBAHA.114.304730