MicroRNA-221-3p promotes pulmonary artery smooth muscle cells proliferation by targeting AXIN2 during pulmonary arterial hypertension

摘要

Pulmonary arterial hypertension (PAH) is a pathological condition characterized by excessive cell proliferation and migration of pulmonary arterial smooth muscle cells (PASMC). PAH pathogenesis shares similarities with cancers such as excessive cell proliferation and apoptosis resistance. A previous study by our group revealed that decreased expression of a tumor suppressor-AXIN2 (Axis inhibition protein 2) was responsible for enhanced PASMC proliferation and suppressed apoptosis. Nevertheless, the mechanisms that regulate the downregulation of AXIN2 in PAH remain elusive. Data from the present study demonstrated that miR-221-3p acts as an upstream regulator of AXIN2 and functions to induce PASMC proliferation. We first showed that miR-221-3p expression was elevated in lung tissue and PASMC of PAH patients as well as in animal models of PAH. Human PASMC were transfected with a miR-221-3p mimic and miR-221-3p inhibitor, respectively, and their effects on the proliferation and migration was assessed using BrdU incorporation, PCNA staining and wound healing assays. In addition, we investigated the molecular mechanism through which miR-221-3p contributes to cell proliferation in PASMC and identified AXIN2 as a direct target gene of miR-221-3p by dual luciferase reporter gene assays, qRT-qPCR and western blotting. Furthermore, we found that ectopic expression of AXIN2 or pharmacological inhibition of beta-catenin by XAV-939 can attenuate the effect of miR-221-3p on cell proliferation in PASMC. Moreover, intravenous injection of miR-221-3p inhibitor attenuated the progression of SU5416-hypoxia-induced PAH in rats. The results of the present study identified a new regulatory axis in which miR-221-3p and AXIN2 regulate the proliferation of PASMC.