Persistent pulmonary hypertension alters the epigenetic characteristics of endothelial nitric oxide synthase gene in pulmonary artery endothelial cells in a fetal lamb model

Physiological Genomics
Xingrao KeGirija G Konduri

Abstract

Decreased expression of endothelial nitric oxide synthase (eNOS), a key mediator of perinatal transition, characterizes persistent pulmonary hypertension of the newborn (PPHN) in neonates and a fetal lamb model; the mechanisms are unclear. We investigated whether increased DNA CpG methylation at the eNOS promoter in estrogen response elements (EREs) and altered histone code together contribute to decreased eNOS expression in PPHN. We isolated pulmonary artery endothelial cells (PAEC) from fetal lambs with PPHN induced by prenatal ductus arteriosus constriction from 128 to 136 days gestation or gestation-matched twin controls. We measured right ventricular systolic pressure (RVSP) and Fulton index and determined eNOS expression in PAEC in control and PPHN lambs. We determined DNA CpG methylation by pyrosequencing and activity of ten eleven translocase demethylases (TET) by colorimetric assay. We quantified the occupancy of transcription factors, specificity protein 1 (Sp1), and estrogen receptors and density of four histone marks around Sp1 binding sites by chromatin immunoprecipitation (ChIP) assays. Fetal lambs with PPHN developed increased RVSP and Fulton index. Levels of eNOS mRNA and protein were decreased in PAEC from PPHN...Continue Reading

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Citations

Jul 25, 2020·Journal of Developmental Origins of Health and Disease·Alejandro Gonzaléz-CandiaEmilio A Herrera
May 11, 2021·Journal of Cardiovascular Pharmacology and Therapeutics·Melanie ReineroGiuseppina Milano
May 18, 2021·Frontiers in Cell and Developmental Biology·Zhi FangQing R Miao

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Methods Mentioned

BETA
Cesarean section
PCR
enzyme linked immunosorbent assay
ELISA
electrophoresis
Assay
immunoprecipitation
ChIP
acetylation
histone acetylation

Software Mentioned

Qiagen
ImageJ
Pyromark Assay Design Software

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