Neonatal exposure to hyperoxia leads to persistent disturbances in pulmonary histone signatures associated with NOS3 and STAT3 in a mouse model

Abstract

BackgroundEarly pulmonary oxygen exposure is one of the most important factors implicated in the development of bronchopulmonary dysplasia (BPD).MethodsHere, we analyzed short- and long-term effects of neonatal hyperoxia on NOS3 and STAT3 expression and corresponding epigenetic signatures using a hyperoxia-based mouse model of BPD.ResultsEarly hyperoxia exposure led to a significant increase in NOS3 (median fold change × 2.37, IQR 1.54–3.68) and STAT3 (median fold change × 2.83, IQR 2.21–3.88) mRNA levels in pulmonary endothelial cells with corresponding changes in histone modification patterns such as H2aZac and H3K9ac hyperacetylation at the respective gene loci. No complete restoration in histone signatures at these loci was observed, and responsivity to later hyperoxia was altered in mouse lungs. In vitro, histone signatures in human aortic endothelial cells (HAEC) remained altered for several weeks after an initial long-term exposure to trichostatin A. This was associated with a substantial increase in baseline eNOS (median 27.2, IQR 22.3–35.6) and STAT3α (median 5.8, IQR 4.8–7.3) mRNA levels with a subsequent significant reduction in eNOS expression upon exposure to hypoxia.ConclusionsEarly hyperoxia induced permanent changes in histones signatures at the NOS3 and STAT3 gene locus might partly explain the altered vascular response patterns in children with BPD.

The Role of Histone Protein Acetylation in Regulating Endothelial Function

“… Postberg et al (2015) also reported the increased acetylation of histone H3K9 and H2A.Z and eNOS expression after hypoxia. Chao et al (2018) further reported that early hypoxia exposure (neonatal exposure to hyperoxia) leads to histone modification patterns as H2A.Z and H3K9 hyperacetylation and a substantial increase of the baseline expression of eNOS and STAT3. This histone modification pattern persists and becomes a signature that alters the response of ECs exposed to hypoxia later ( Chao et al, 2018 ).…”

“… Chao et al (2018) further reported that early hypoxia exposure (neonatal exposure to hyperoxia) leads to histone modification patterns as H2A.Z and H3K9 hyperacetylation and a substantial increase of the baseline expression of eNOS and STAT3. This histone modification pattern persists and becomes a signature that alters the response of ECs exposed to hypoxia later ( Chao et al, 2018 ). In contrast, eNOS expression is decreased in another PPHN model induced by prenatal ductus arteriosus constriction in lamb.…”

Short-term perinatal oxygen exposure may impair lung development in adult mice

“…The study is limited by the lack of exposure to oxygen at birth that usually occurs in infants requiring resuscitation. Early hyperoxia may induce changes in histone signatures in gene expression, altering vascular patterns in infants with BPD [ 48 ]. The timing, duration, and severity of hyperoxia relative to resuscitation need critical exploration.…”

MicroRNA-214 Prevents Pulmonary Angiogenesis and Alveolarization in Rat Models with Bronchopulmonary Dysplasia via PlGF-Dependent STAT3 Signaling Pathway

“…PlGF has also been proved to accelerate the phosphorylation of STAT3 [12]. Moreover, neonatal exposure to hyperoxia has been found to lead to a signi cant increase of the signal transducer and activator of transcription 3 (STAT3) mRNA expression in pulmonary endothelial cells [13]. In this regard, we hypothesized that a regulatory network of miR-214/PlGF/STAT3 signaling pathway may be involved in BPD.…”