FGF21 attenuates pulmonary arterial hypertension via downregulation of miR-130, which targets PPARγ.
FGF21 attenuates pulmonary arterial hypertension via downregulation of miR-130, which targets PPARγ.
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FGF21 通过下调 miR-130（针对 PPARγ）来减轻肺动脉高压
DOI：
10.1111/jcmm.17154
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发表时间：
2022-03
影响因子：
5.3
通讯作者：
Huang X
中科院分区：
文献类型：
--
作者：
Wang M;Su L;Sun J;Cai L;Li X;Zhu X;Song L;Li J;Tong S;He Q;Cai M;Yang L;Chen Y;Wang L;Huang X
肺动脉平滑肌细胞(PASMCs)的增殖、迁移和抗凋亡在肺动脉高压(PAH)的发生发展中起重要作用。我们先前的研究发现，成纤维细胞生长因子21(FGF21)调节信号通路分子，如过氧化物酶体增殖物激活受体γ(PPARγ)，在PAH的治疗中发挥重要作用。然而，miRNAs在这些效应中的生物学作用尚不清楚。在本研究中，我们利用miRNA测序和实时荧光定量聚合酶链式反应，发现FGF21处理抑制了体内和体外低氧诱导的PAH中miR-130的上调。双荧光素酶报告基因分析表明，miR130直接负调控PPARγ的表达。抑制miR130的表达可抑制缺氧PASMC的异常增殖、迁移和抗凋亡作用，这种作用在PPARγ被敲除后被纠正。外源性应用miR-130agomir后，观察FGF21对肺血管重塑的改善作用以及对PASMCs增殖、迁移和抗凋亡的抑制作用。综上所述，本研究通过对miR130/PPARγ轴的调节，揭示了FGF21对PAH的保护作用及其机制，为基于FGF21的PAH潜在药物的开发提供了新的思路。
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.
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