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FGF21 attenuates pulmonary arterial hypertension via downregulation of miR-130, which targets PPARγ.

ABSTRACT: 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.

SUBMITTER: Wang M

PROVIDER: S-EPMC8831951 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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FGF21 attenuates pulmonary arterial hypertension via downregulation of miR-130, which targets PPARγ.

Wang Meibin M Su Lihuang L Sun Junwei J Cai Luqiong L Li Xiuchun X Zhu Xiayan X Song Lanlan L Li Jingyin J Tong Shuolan S He Qinlian Q Cai Mengsi M Yang Lehe L Chen Yanfan Y Wang Liangxing L Huang Xiaoying X

Journal of cellular and molecular medicine 20220106 4

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 ...[more]

PMID: 34989130

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Project description:MicroRNAs (miRs) are reported to serve key roles in pulmonary arterial hypertension (PAH). miR‑1 has been found in cardiovascular diseases. The present study aimed to determine whether the knockdown of miR‑1 could inhibit right ventricle (RV) remodeling and thereby control PAH in model rats. PAH model rats were established by exposing rats to hypoxia, while cardiac fibroblasts (CFs) obtained from PAH model rats were treated with hypoxia to establish an in vitro model, and RV remodeling was evaluated by Masson staining and the levels of collagen I, collagen III, α‑smooth muscle actin (α‑SMA) and connective tissue growth factor (CTGF) evaluated by western blotting or reverse transcription‑quantitative PCR. The results revealed that the expression levels of miR‑1 were upregulated in the RV of PAH model rats induced with hypoxia and in the CFs treated with hypoxia. The mean pulmonary arterial pressure, RV systolic pressure, RV/(left ventricle + interventricular septum) and RV/tibia length were increased in PAH rats; however, the increases in all parameters were subsequently reversed by transfection with a miR‑1 antagomiR in PAH model rats. The transfection with the miR‑1 antagomiR inhibited the development of RV fibrosis and downregulated the mRNA expression levels of collagen I, collagen III, α‑SMA and CTGF in the RV tissue of PAH model rats. The upregulation of collagen I, collagen III, α‑SMA and CTGF expression levels in hypoxia‑treated CFs was also subsequently reversed by miR‑1 antagomiR transfection. The expression levels of collagen I, collagen III, α‑SMA and CTGF were also upregulated in the CFs obtained from PAH model rats, and these increases were attenuated by miR‑1 antagomiR transfection. The expression levels of phosphorylated (p)‑PI3K and p‑AKT were also upregulated in hypoxia‑treated CFs, and these increases were also inhibited by transfection with miR‑1 antagomiR. In conclusion, these results indicated that inhibiting miR‑1 may attenuate RV hypertrophy and fibrosis in PAH model rats, a mechanism that may involve the PI3K/AKT signaling pathway.

Dataset Information

FGF21 attenuates pulmonary arterial hypertension via downregulation of miR-130, which targets PPARγ.

Publications

FGF21 attenuates pulmonary arterial hypertension via downregulation of miR-130, which targets PPARγ.

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