miRNA-34a promotes proliferation of human pulmonary artery smooth muscle cells by targeting PDGFRA

ObjectivesPulmonary arterial hypertension (PAH) is a fast progressing vascular disease characterized by uncontrolled cell proliferation of pulmonary artery smooth muscle cells (PASMCs). Some studies have suggested that PAH and cancers share an apoptosis-resistant state, featuring excessive cell proliferation. The miR-34 family consists of tumour-suppressive miRNAs, and its reduced expression has been reported in numerous cancers; however, its role in hypoxia-induced PAH has not been previously studied. Materials and methodsmiR-34 family expression was evaluated in a rat model with hypoxia and in cultured hypoxic PASMCs, using real-time quantitative PCR (RT-qPCR). Function of miR-34 family was assessed by transfecting miR-34 mimics and inhibitors. Dual luciferase reporter gene assays, RT-qPCR and Western blotting were performed to validate target genes of miR-34. ResultsSignificant down-regulation of miR-34a in hypoxic lung tissue, pulmonary artery and PASMCs was identified and then effects of miR-34a in modulating cell proliferation in human pulmonary artery smooth muscle cells (hPASMCs) was investigated in vitro. Reduction of miR-34a levels in hPASMCs caused increased proliferation and these effects were reversed by overexpression of miR-34a. miR-34a overexpression down-regulated platelet-derived growth factor receptor alpha (PDGFRA) expression, which is a key factor in PAH development. These results suggest that miR-34a is a potential regulator of proliferation in PASMCs, and that it could be used as a novel treatment strategy in PAH.