Snhg18 promotes hypoxic pulmonary hypertension by enhancing glycolysis

Pulmonary hypertension (PH) is a life-threatening vascular disorder characterized by progressive pulmonary vascular remodeling. Emerging evidence has indicated that long non-coding RNAs (lncRNAs) play vital roles in the pathogenesis of PH. In this study, we aim to clarify the role of lncRNA small nucleolar RNA host gene 18 (Snhg18) in pulmonary vascular remodeling and investigate its underlying mechanisms.

Differential gene expression was detected by qRT-PCR and Western blot assays. CCK-8, EdU, transwell assays, and the in vivo pulmonary hypertension model were used to investigate the effect of Snhg18 on pulmonary hypertension. Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP) assay, RNA pull-down, and transcriptome sequencing were employed to explore the mechanism by which Snhg18 functions in pulmonary hypertension.

LncRNA Snhg18 is upregulated in pulmonary artery smooth muscle cells (PASMCs) and lung tissues under hypoxic conditions. Inhibition of Snhg18 attenuates cell proliferation in vitro and in vivo. Mechanistically, copy number amplification promotes the expression of Snhg18 at the genomic level, and the transcription factor Sp1 activates Snhg18 transcription by binding to its promoter. Furthermore, Snhg18 interacts with the m6A "reader" protein heterogeneous nuclear ribonucleoprotein A2/B1 (Hnrnpa2b1), thus increasing the stability of enolase 3 (Eno3) mRNA in an m6A-dependent manner. The elevation of Eno3 augments glycolysis in PASMCs, thus promoting cell proliferation and vascular remodeling.

Our study demonstrates the important role of Snhg18/Hnrnpa2b1/Eno3 axis in pulmonary vascular remodeling, and provides a potential novel therapeutic target for PH.