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

Yuhao Zhang,Xiaoyu Dong,Krithika Lingappan

doi:10.1155/2019/8327486

Yuhao Zhang, Xiaoyu Dong + Show 1 more

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https://doi.org/10.1155/2019/8327486

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Abstract

Bronchopulmonary dysplasia (BPD) is characterized by a severe impairment in lung alveolarization and vascular development. We have previously shown that pulmonary angiogenesis is preserved in hyperoxia-exposed female mice accompanied by increased miR-30a expression, which is a proangiogenic miRNA. Also, miR-30a expression is decreased in human BPD. HIF-1α plays an essential role in postnatal lung development, especially in recovery from hyperoxic injury. Snai1 activation promotes pathological fibrosis through many mechanisms including Endo-MT, which may in turn adversely impact lung vascular development. Our objective was to test the hypothesis that higher miR-30a expression through HIF-1α decreases Snai1 expression in females and attenuates injury in the developing lung. Neonatal male and female mice (C57BL/6) were exposed to hyperoxia (P1-5, 0.95 FiO2) and euthanized on P21. Neonatal human pulmonary microvascular endothelial cells (HPMECs; 18-24-week gestation donors; 3/group either sex) were subjected to hyperoxia (95% O2 and 5% CO2) or normoxia (air and 5% CO2) up to 72 h. Snai1 expression was measured in HPMECs in vitro and in neonatal mouse lungs in vivo. Also, Snai1 expression was measured in HPMECs after miR-30a mimic and miR-30a inhibitor treatment. To further establish the potential regulation of miR-30a by Hif-1α, miR-30a expression after Hif-1α inhibition was measured in HPMECs. In vivo, Snai1 expression was decreased in neonatal female lungs compared to males at P7. Increased Snai1 expression was seen in male HPMECs upon exposure to hyperoxia in vitro. Treatment with the miR-30a mimic decreased Snai1 expression in HPMECs, while miR-30a inhibition significantly increased Snai1 expression in HPMECs. siRNA-mediated loss of Hif-1α expression in HPMECs decreased miR-30a expression. Hif-1α may lead to differential sex-specific miR-30a expression and may contribute to protection from hyperoxic lung injury in female neonatal mice through decreased Snai1 expression.

Highlights

With the increasing survival of extremely premature babies, the incidence of bronchopulmonary dysplasia (BPD) has remained steady, despite the advances in neonatal intensive care
WT male and female neonatal mice were exposed to hyperoxia (0.95 FiO2 from P1-5) during the saccular stage of lung development, and Snai1 mRNA and protein expression were measured at P7 and P21 and compared to respective normoxic controls
Sex-specific differences exist in many neonatal morbidities including bronchopulmonary dysplasia (BPD), which adversely affects a significant number of extremely premature newborns

Summary

Introduction

With the increasing survival of extremely premature babies, the incidence of bronchopulmonary dysplasia (BPD) has remained steady, despite the advances in neonatal intensive care. Murine models have utilized varying durations of postnatal hyperoxia exposure to simulate the human disease in neonatal mice [1, 2]. Bronchopulmonary dysplasia (BPD) is characterized mainly by an arrest in lung development with severe impairment of alveolar septation and vascular development, and pathological fibrosis in severe cases [3,4,5,6]. BPD disproportionately affects male infants compared to females. We have previously shown that alveolarization and pulmonary angiogenesis is preserved in hyperoxia-exposed female neonatal mice compared to males [8]. MiR-30a has proangiogenic, antiinflammatory, and antifibrotic effects in many diseases processes [10,11,12,13,14,15,16,17], including those affecting the lung.

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