Sex-specific differences in the modulation of Growth Differentiation Factor 15 (GDF15) by hyperoxia in vivo and in vitro : Role of Hif-1α

Abstract

Male premature neonates are more susceptible than females to the development of bronchopulmonary dysplasia (BPD). The reasons underlying sexually dimorphic outcomes in premature neonates are not known. GDF15 (Growth and differentiation factor 15) is a secreted cytokine and plays a role in cell proliferation, apoptosis, and angiogenesis. In this study, we sought to elucidate the sex-specific expression of Gdf15 in the lung in vivo in neonatal hyperoxic lung injury and its regulation by Hif-1α, and to delineate the differences in GDF15 expression in male and female human umbilical venous endothelial cells in an in vitro model of oxygen toxicity. Following hyperoxia exposure (95% FiO2, PND (postnatal day 1-5: saccular stage of lung development), neonatal male mice (C57BL/6) show increased GDF15 and decreased HIF-1α expression compared to female mice. For the in vitro experiments, male and female HUVECs were exposed to room air condition (21% O2, 5% CO2) or in hyperoxia condition (95% O2, 5% CO2) for up to 72 h. Male HUVECs had greater expression of GDF15 mRNA and protein. To study the inter-relationship between GDF15 and HIF-1α, we measured the expression of GDF15 in H441 cells after HIF-1α knockdown using promoter dual luciferase reporter assay, which showed that HIF-1α and GDF15 expression are inversely related under normoxia and hyperoxia. The results indicate that sex differences exist in the expression and modulation of GDF15 by HIF-1α in neonatal hyperoxic injury both in vivo and in vitro. These differences could explain in part the mechanisms behind sex-specific differences in BPD.

Role of HIF-1α-miR30a-Snai1 Axis in Neonatal Hyperoxic Lung Injury

“…We have previously shown that Hif-1α expression was increased in female mice at P7 and decreased in male mice at P21 after hyperoxia exposure [29] and that HIF-1α binding to its target genes is more significant in female lungs after hyperoxia exposure [22]. HIF-1 α protein expression was decreased in both male and female HUVECs upon exposure to hyperoxia [29]. Motif analysis revealed a hypoxia response element (HRE) [AG]CGTG site 428 base pairs upstream of miR-30a (Figure 4(a)).…”

The role of GDF15 in bone metastasis of lung adenocarcinoma cells

“…However, as a distant relative of the TGF-β superfamily, GDF15 is similar to other family members, as it plays a complex but not yet fully studied role in various tumors. GDF15 was revealed to be negatively correlated with the expression of hypoxia-inducible factor α (HIF-1α) in mice (37), whereas the activated HIF-1α signaling pathway increased intracellular VEGF levels (38). It is well known that VEGF can drive tumor growth and metastasis by promoting angiogenesis.…”

Redistribution of Extracellular Superoxide Dismutase Causes Neonatal Pulmonary Vascular Remodeling and PH but Protects Against Experimental Bronchopulmonary Dysplasia

“…It is possible that we are missing subtle abnormalities in alveolarization at earlier time points in the R 213 G mice that have resolved with compensatory alveolar growth by 22 days of life, as is seen in some preterm infants with BPD who demonstrate improved airway abnormalities over time [ 54 , 55 ]. Sex differences are increasingly recognized as important in disease susceptibility, and have been demonstrated in neonatal hyperoxic lung injury as well as bleomycin induced lung injury in aged adult mice but not young adult mice [ 56 , 57 ]. While our preliminary analysis does not show a signal for any differences between sex at baseline or after exposure, we do not have a sufficient number of mice in each group to conclusively determine sex differences.…”