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FGF21 attenuates pulmonary arterial hypertension via downregulation of miR-130, which targets PPARγ
Meibin Wang1, Lihuang Su1, Junwei Sun1
1Division of Pulmonary Medicine, Key Laboratory of Heart and Lung, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
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.
Insights
Fibroblast growth factor 21 (FGF21) treats pulmonary arterial hypertension (PAH) by regulating miR-130 and peroxisome proliferator-activated receptor gamma (PPARγ). This pathway inhibits pulmonary artery smooth muscle cell proliferation, migration, and survival, offering new therapeutic strategies for PAH.
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Cell Biology
Background:
- Pulmonary arterial hypertension (PAH) involves pulmonary artery smooth muscle cell (PASMC) proliferation, migration, and resistance to apoptosis.
- Fibroblast growth factor 21 (FGF21) has shown potential in PAH treatment by modulating signaling pathways like peroxisome proliferator-activated receptor gamma (PPARγ).
- The role of microRNAs (miRNAs) in FGF21's effects on PAH remains unclear.
Purpose of the Study:
- To investigate the role of miRNAs in FGF21-mediated regulation of PASMCs in PAH.
- To elucidate the molecular mechanism by which FGF21 impacts PAH progression via the miR-130/PPARγ axis.
- To evaluate the therapeutic potential of targeting the miR-130/PPARγ pathway in PAH.
Main Methods:
- miRNA sequencing and real-time PCR to identify miRNA expression changes in hypoxia-induced PAH.
- Dual luciferase reporter gene assays to confirm direct interaction between miR-130 and PPARγ.
- In vitro and in vivo studies using PASMCs and animal models of PAH.
- Exogenous administration of miR-130 agomir to assess therapeutic effects.
Main Results:
- FGF21 treatment inhibited the elevation of miR-130 in hypoxia-induced PAH models.
- miR-130 directly targets and negatively regulates PPARγ expression.
- Inhibition of miR-130 suppressed abnormal PASMC proliferation, migration, and apoptotic resistance.
- PPARγ knockdown reversed the effects of miR-130 inhibition on PASMCs.
- Exogenous miR-130 agomir mimicked the therapeutic effects of FGF21 on pulmonary vascular remodeling and PASMC dysfunction.
Conclusions:
- FGF21 exerts protective effects against PAH by regulating the miR-130/PPARγ axis.
- This study reveals a novel molecular mechanism underlying FGF21's action in PAH.
- Targeting the miR-130/PPARγ pathway presents a promising therapeutic strategy for PAH treatment.
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