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Long non-coding RNAs (lncRNAs) play a significant role in pulmonary hypertension (PH). Our preliminary data showed that hypoxia-induced PH is attenuated by fibroblast growth factor 21 (FGF21) administration. Therefore, we further investigated the regulatory role of long non-coding RNAs in PH treated with FGF21. RNA sequencing analysis and real-time PCR identified a significantly up-regulation of the H19 after FGF21 administration. Moreover, gain- and loss-of-function assays demonstrated that FGF21 suppressed hypoxia-induced proliferation of pulmonary artery smooth muscle cells partially through upregulation of H19. In addition, FGF21 deficiency markedly exacerbated hypoxia-induced increases of pulmonary artery pressure and pulmonary vascular remodelling. In addition, AAV-mediated H19 overexpression reversed the malignant phenotype of FGF21 knockout mice under hypoxia expose. Further investigation uncovered that H19 also acted as an orchestra conductor that inhibited the function of mechanistic target of rapamycin complex 1 (mTORC1) by disrupting the interaction of mTORC1 with eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1). Our work highlights the important role of H19 in PH treated with FGF21 and suggests a mechanism involving mTORC1/EIF4EBP1 inhibition, which may provide a fundamental for clinical application of FGF21 in PH., (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Impact Statement: In this study, we reported for the first time that FGF21 alleviated hypoxia-induced pulmonary hypertension through attenuation of increased pulmonary arterial pressure, pulmonary arterial remodeling and collagen deposition in vivo, and we confirmed the mutual promotion of FGF21 and PPARγ in hypoxia-induced pulmonary hypertension. Additionally, we found that FGF21 and PPARγ mutually promote each other's expression via the AMPK/PGC-1α pathway and KLB protein in vitro and in vivo. Pulmonary hypertension is a progressive and serious pathological phenomenon with a poor prognosis, and current therapies are highly limited. Our results provide novel insight into potential clinical therapies for pulmonary hypertension and establish the possibility of using this drug combination and potential dosage reductions in clinical settings.

The proliferation, migration and apoptotic resistance of pulmonary artery smooth muscle cells (PASMCs) are central to the progression of pulmonary arterial hypertension (PAH). Our previous study identified that fibroblast growth factor 21 (FGF21) regulates signalling pathway molecules, such as peroxisome proliferator‐activated receptor gamma (PPARγ), to play an important role in PAH treatment. However, the biological roles of miRNAs in these effects are not yet clear. In this study, using miRNA sequencing and real‐time PCR, we found that FGF21 treatment inhibited miR‐130 elevation in hypoxia‐induced PAH in vitro and in vivo. Dual luciferase reporter gene assays showed that miR‐130 directly negatively regulates PPARγ expression. Inhibition of miR‐130 expression suppressed abnormal proliferation, migration and apoptotic resistance in hypoxic PASMCs, and this effect was corrected upon PPARγ knockdown. Both the ameliorative effect of FGF21 on pulmonary vascular remodelling and the inhibitory effect on proliferation, migration and apoptotic resistance in PASMCs were observed following exogenous administration of miR‐130 agomir. In conclusion, this study revealed the protective effect and mechanism of FGF21 on PAH through regulation of the miR‐130/PPARγ axis, providing new ideas for the development of potential drugs for PAH based on FGF21. [ABSTRACT FROM AUTHOR]