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miR-140-3p Alleviates Pulmonary Arterial Smooth Muscle Cell Dysfunction via MAP2K6/p38 Pathway
Ling Chen1,2, Jia-Yi Zhang1, Lei Huang1
1Department of Pulmonary & Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China.
Abstract:
Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling arising from aberrant proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs). Recent studies indicate that miR-140-3p plays a significant role in cell proliferation and apoptosis. However, whether miR-140-3p involves in the development of PAH remains unknown. In this study, we showed that the expressions of miR-140-3p in SU5416/hypoxia (SuHx)-induced PAH and hypoxia-treated human PASMCs were significantly downregulated. Administration of the rno-miR-140-3p agomir significantly alleviated right ventricular systolic pressure, pulmonary vascular remodeling, and right ventricular hypertrophy in PAH. In cultured PASMCs, transfected with miR-140-3p mimics effectively inhibited hypoxia-induced cell proliferation and migration, while facilitated cell apoptosis. Conversely, suppression of miR-140-3p activity by its inhibitors exerted the opposite effects. Dual-luciferase reporter assay showed that miR-140-3p targeted the 3'-UTR of the mRNA of MAP2K6, thus decreased transcripts and its protein expression, and thereafter inhibited the phosphorylation activation of p38. Moreover, upregulation of MAP2K6 counteracted the inhibitory effect of miR-140-3p on matrix metalloproteinase 2/9 (MMP2/9) expression and pro-apoptotic effects as indicated by Bcl2/BAX in hypoxia-treated human PASMCs. Collectively, our findings highlighted the therapeutic potential of miR-140-3p in PAH and revealed a regulatory mechanism involving the miR-140-3p/MAP2K6/p38 axis.
Insights
MicroRNA-140-3p is downregulated in pulmonary arterial hypertension (PAH). Restoring miR-140-3p levels inhibits PASMC proliferation and alleviates PAH, revealing a novel therapeutic target.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Gene Regulation
Background:
- Pulmonary arterial hypertension (PAH) involves pulmonary vascular remodeling driven by pulmonary artery smooth muscle cell (PASMC) proliferation and apoptosis resistance.
- MicroRNAs (miRNAs) are implicated in cell proliferation and apoptosis, but miR-140-3p's role in PAH is unexplored.
Purpose of the Study:
- To investigate the role of miR-140-3p in the pathogenesis of pulmonary arterial hypertension (PAH).
- To elucidate the molecular mechanisms underlying miR-140-3p's function in PASMCs.
Main Methods:
- Assessed miR-140-3p expression in SU5416/hypoxia (SuHx)-induced PAH models and hypoxia-treated human PASMCs.
- Administered miR-140-3p agomir in vivo and utilized miR-140-3p mimics/inhibitors in vitro.
- Performed dual-luciferase reporter assays to identify miR-140-3p targets.
- Analyzed downstream signaling pathways including MAP2K6, p38, MMP2/9, Bcl2, and BAX.
Main Results:
- miR-140-3p expression was significantly downregulated in PAH models and hypoxia-treated PASMCs.
- miR-140-3p agomir administration ameliorated PAH symptoms, including right ventricular systolic pressure and vascular remodeling.
- miR-140-3p suppressed hypoxia-induced PASMC proliferation and migration while promoting apoptosis.
- miR-140-3p directly targeted MAP2K6, inhibiting the MAP2K6/p38 pathway and affecting MMP2/9 and Bcl2/BAX expression.
Conclusions:
- miR-140-3p plays a protective role in PAH by inhibiting PASMC proliferation and promoting apoptosis.
- The miR-140-3p/MAP2K6/p38 signaling axis is a key regulatory mechanism in PAH pathogenesis.
- miR-140-3p represents a promising therapeutic target for treating pulmonary arterial hypertension.
