Abstract
BackgroundThe incidence of bronchopulmonary dysplasia (BPD), a chronic lung disease of newborns, has been paradoxically rising despite medical advances. Histone deacetylase 3 (Hdac3) has been reported to be a crucial regulator in alveologenesis. Hence, this study aims to investigate the mechanism of Hdac3 in the abnormal pulmonary angiogenesis and alveolarization of BPD.MethodsA hyperoxia-induced BPD model of was developed in newborn mice, and primary lung fibroblasts were isolated from adult mice. Hdac3 was knocked out in vivo and knocked down in vitro, while microRNA (miR)-17 was downregulated in vivo and in vitro to clarify their roles in abnormal pulmonary angiogenesis and alveolarization. Mechanistic investigations were performed on the interplay of Hdac3, miR-17-92 cluster, enhancer of zeste homolog 1 (EZH1), p65 and placental growth factor (Pgf).ResultsHdac3 was involved in abnormal alveolarization and angiogenesis in BPD mice. Further, the expression of the miR-17-92 cluster in BPD mice was downregulated by Hdac3. miR-17 was found to target EZH1, and Hdac3 rescued the inhibited EZH1 expression by miR-17 in lung fibroblasts. Additionally, EZH1 augmented Pgf expression by recruiting p65 thus enhancing the progression of BPD. Hdac3 augmented the recruitment of p65 in the Pgf promoter region through the miR-17/EZH1 axis, thus enhancing the transcription and expression of Pgf, which elicited abnormal angiogenesis and alveolarization of BPD mice.ConclusionsAltogether, the present study revealed that Hdac3 activated the EZH1-p65-Pgf axis through inhibiting miR-17 in the miR-17-92 cluster, leading to accelerated abnormal pulmonary angiogenesis and alveolarization of BPD mice.
Highlights
The incidence of bronchopulmonary dysplasia (BPD), a chronic lung disease of newborns, has been paradoxically rising despite medical advances
Abundant Histone deacetylase 3 (Hdac3) expression accelerates the progression of BPD Previous literature has reported that Hdac3 participated in the remodeling and expansion of distant alveolar vesicles into primitive pulmonary alveolus by downregulating the miR-17-92 cluster (Wang et al 2016), which commonly constitutes to the occurrence of BPD in premature infants (Ruiz-Camp et al 2019)
The degree of abnormal alveolarization in BPD mice was subsequently examined and the results showed that the mean linear intercept (MLI) of alveoli in BPD mice was higher than that of the control mice, while the number of alveoli was less than that of the control mice (Fig. 1b)
Summary
The incidence of bronchopulmonary dysplasia (BPD), a chronic lung disease of newborns, has been paradoxically rising despite medical advances. This study aims to investigate the mechanism of Hdac in the abnormal pulmonary angiogenesis and alveolarization of BPD. Bronchopulmonary dysplasia (BPD) is a common chronic lung disease characterized by arrested alveolar development or loss of alveoli which commonly occurs in. Histone deacetylases (HDACs) are chromatin-modifying enzymes that have emerged as the important targets for treating various diseases due to their powerful regulatory role in physiological and pathological settings (Cantley et al 2017). The miR-17-92 cluster (miR-17, miR-18a, miR-19a, miR-19b, miR-20a, and miR-92) has been reported to be poorly expressed in lung tissues of BPD infants, while the downregulation of miR-17-92 cluster was closely related to the development of BPD (Rogers et al 2015)
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