Antenatal hypoxia induces epigenetic repression of glucocorticoid receptor and promotes ischemic-sensitive phenotype in the developing heart

Journal of Molecular and Cellular Cardiology
Fuxia XiongLubo Zhang

Abstract

Large studies in humans and animals have demonstrated a clear association of an adverse intrauterine environment with an increased risk of cardiovascular disease later in life. Yet mechanisms remain largely elusive. The present study tested the hypothesis that gestational hypoxia leads to promoter hypermethylation and epigenetic repression of the glucocorticoid receptor (GR) gene in the developing heart, resulting in increased heart susceptibility to ischemia and reperfusion injury in offspring. Hypoxic treatment of pregnant rats from day 15 to 21 of gestation resulted in a significant decrease of GR exon 14, 15, 16, and 17 transcripts, leading to down-regulation of GR mRNA and protein in the fetal heart. Functional cAMP-response elements (CREs) at -4408 and -3896 and Sp1 binding sites at -3425 and -3034 were identified at GR untranslated exon 1 promoters. Hypoxia significantly increased CpG methylation at the CREs and Sp1 binding sites and decreased transcription factor binding to GR exon 1 promoter, accounting for the repression of the GR gene in the developing heart. Of importance, treatment of newborn pups with 5-aza-2'-deoxycytidine reversed hypoxia-induced promoter methylation, restored GR expression and prevented hypoxia...Continue Reading

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Citations

May 3, 2018·Physiological Reviews·Charles A DucsayLubo Zhang
Oct 12, 2019·Cells·Bing LiuJulie E Goodwin
Apr 25, 2019·The Journal of Endocrinology·Rui SongLubo Zhang
Sep 26, 2020·Frontiers in Aging Neuroscience·Guofang ShenQingyi Ma
Jul 13, 2018·Frontiers in Physiology·Emily J CammAmanda N Sferruzzi-Perri
Nov 25, 2020·Clinical Science·Stephane L Bourque, Sandra T Davidge
Jul 19, 2021·The Journal of Steroid Biochemistry and Molecular Biology·Roza MotavalliJalal Etemadi
Aug 8, 2021·International Journal of Molecular Sciences·Elena Rybnikova, Natalia Nalivaeva
Sep 28, 2018·Pediatrics·Barry M LesterCarmen J Marsit

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