miR-140-3p Alleviates Pulmonary Arterial Smooth Muscle Cell Dysfunction via MAP2K6/p38 Pathway

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.