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Mol Ther. 2019 Aug 22. pii: S1525-0016(19)30370-3. doi: 10.1016/j.ymthe.2019.07.022. [Epub ahead of print]

Long Noncoding RNA-Maternally Expressed Gene 3 Contributes to Hypoxic Pulmonary Hypertension.

Author information

1
Department of Pharmacology, Harbin Medical University-Daqing, Daqing, Heilongjiang 163319, P.R. China.
2
Department of Genetics and Cell Biology, Harbin Medical University-Daqing, Daqing, Heilongjiang 163319, P.R. China. Electronic address: zhengxiaodong@hmudq.edu.cn.
3
College of Pharmacy, Harbin Medical University, Harbin, 150081, P.R. China.
4
College of Pharmacy, Harbin Medical University, Harbin, 150081, P.R. China; Department of Pharmaceutical, Harbin Medical University-Daqing, Daqing, Heilongjiang 163319, P.R. China.
5
Department of Pharmaceutical, Harbin Medical University-Daqing, Daqing, Heilongjiang 163319, P.R. China.
6
Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China.
7
College of Pharmacy, Harbin Medical University, Harbin, 150081, P.R. China; Central Laboratory of Harbin Medical University-Daqing, Daqing 163319, P.R. China; State Province Key Laboratories of Biomedicine-Pharmaceutics of China, Daqing 163319, P.R. China; Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, Harbin Medical University, Harbin, 150081, P.R. China. Electronic address: dalingz@yahoo.com.

Abstract

The expression and function of long noncoding RNAs (lncRNAs) in the development of hypoxic pulmonary hypertension (HPH), especially in the proliferation of pulmonary artery smooth muscle cells (PASMCs), are largely unknown. Herein, we examined the expression and role of lncRNA-maternally expressed gene 3 (lncRNA-MEG3) in HPH. lncRNA-MEG3 was significantly increased and primarily localized in the cytoplasm of hypoxic PASMCs. lncRNA-MEG3 knockdown by lung-specific delivery of small interfering RNAs (siRNAs) significantly inhibited the development of HPH in vivo. Silencing of lncRNA-MEG3 by siRNAs and gapmers attenuated proliferation and cell-cycle progression in both PASMCs from idiopathic pulmonary arterial hypertension (iPAH) patients (iPAH-PASMCs) and hypoxia-exposed PASMCs in vitro. Mechanistically, we found that lncRNA-MEG3 interacts with and leads to the degradation of microRNA-328-3p (miR-328-3p), leading to upregulation of insulin-like growth factor 1 receptor (IGF1R). Additionally, higher expression of lncRNA-MEG3 and IGF1R and lower expression of miR-328-3p were observed in iPAH-PASMCs and relevant HPH models. These data provide insights into the contribution of lncRNA-MEG3 to HPH. Upregulation of lncRNA-MEG3 sequesters cytoplasmic miR-328-3p, eventually leading to expression of IGF1R, revealing a regulatory mechanism by lncRNAs in hypoxia-induced PASMC proliferation.

KEYWORDS:

hypoxic pulmonary hypertension; insulin-like growth factor 1 receptor; maternally expressed gene 3; microRNA-328; noncoding RNA; proliferation

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