Involvement of Hdac3-mediated inhibition of microRNA cluster 17-92 in bronchopulmonary dysplasia development
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(2020) 26:99 Wang et al. Mol Med https://doi.org/10.1186/s10020-020-00237-4
Open Access
RESEARCH ARTICLE
Involvement of Hdac3‑mediated inhibition of microRNA cluster 17‑92 in bronchopulmonary dysplasia development Di Wang1, Hui Hong2, Xiao‑Xia Li2, Jing Li2 and Zhi‑Qun Zhang2*
Abstract Background: The 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 regu‑ lator in alveologenesis. Hence, this study aims to investigate the mechanism of Hdac3 in the abnormal pulmonary angiogenesis and alveolarization of BPD. Methods: A 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 ). Results: Hdac3 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 abnor‑ mal angiogenesis and alveolarization of BPD mice. Conclusions: Altogether, 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. Keywords: Histone deacetylase 3, microRNA-17-92 cluster, Placental growth factor, Bronchopulmonary dysplasia, Pulmonary angiogenesis, Alveolarization Background Bronchopulmonary dysplasia (BPD) is a common chronic lung disease characterized by arrested alveolar development or loss of alveoli which commonly occurs in *Correspondence: [email protected] 2 Department of Neonatology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, No. 261, Huansha Road, Hangzhou 310006, Zhejiang, People’s Republic of China Full list of author information is available at the end of the article
premature infants. BPD is associated with increased risks of morbidity and mortality, as well as adverse neurodevelopmental outcomes among prematurely born infants (Gallini et al. 2014; Thebaud and Abman 2007). Risk factors responsible for BPD include pre- and postnatal infections, hyperoxia, as well as mechanical ventilation, which not only influence the interacted function of proand anti-inflammatory proteins, but also the
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