Abstract
BackgroundAbnormal proliferation of pulmonary artery smooth muscle cells (PASMCs) is a key mechanism in pulmonary arterial hypertension (PAH). Serotonin (5-hydroxytryptamine, 5-HT) can induce abnormal proliferation of PASMCs. The role of miR-361-3p in serotonin-induced abnormal PASMCs proliferation remains unclear.MethodsThe miR-361-3p level was analyzed in plasma from PAH patients and normal controls and in human PASMCs (hPASMCs) using RT-PCR. The hPASMCs were transfected with an miR-361-3p mimic and then treated with serotonin. Untransfected hPASMCs were used as the control. Cell proliferation was evaluated using an MTS assay and 5-ethynyl-2′-deoxyuridine (EdU) staining. The cell cycle stages were evaluated using flow cytometry. The association between miR-361-3p and serotonin transporter (SERT) was determined using a luciferase reporter assay and anti-AGO2 RNA immunoprecipitation assay. The protein expression was evaluated via western blotting.ResultsThe miR-361-3p level was lower in plasma from PAH patients than in plasma from the any of the normal control subjects. The mean pulmonary arterial pressure, pulmonary vascular resistance and pulmonary vascular resistance index were higher in PAH patients whose miR-361-3p level was lower than the median value for patients than in those whose miR-361-3p level was higher than the median. Serotonin treatment reduced miR-361-3p expression in the hPASMCs. MiR-361-3p overexpression suppressed cell proliferation, promoted apoptosis, induced G1 arrest, and decreased the phosphorylation level of ERK1/2 in serotonin-treated hPASMCs. SERT was identified as an miR-361-3p target. Its overexpression alleviated the effect of miR-361-3p overexpression on serotonin-induced hPASMC proliferation and upregulation of phosphorylated ERK1/2.ConclusionsThe miR-361-3p level is lower in the plasma of PAH patients. Upregulation of miR-361-3p suppresses serotonin-induced proliferation of hPASMCs by targeting SERT. Our results suggest that miR-361-3p is a potential therapeutic target in PAH.
Highlights
Abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs) is a key mechanism in pulmonary arterial hypertension (PAH)
Our results suggest that miR-361-3p is a potential therapeutic target in PAH
The OD490nm value of human PASMCs (hPASMCs) treated with 250, 500 and 1000 μmol/l serotonin for 24, 48 and 72 h was significantly higher than that of hPASMCs not treated with serotonin (Fig. 1e), indicating that serotonin treatment increases the proliferation of hPASMCs
Summary
Abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs) is a key mechanism in pulmonary arterial hypertension (PAH). Pulmonary arterial hypertension (PAH) is associated with pathophysiological changes in the pulmonary arteries, including vasoconstriction, vascular remodeling due to abnormal proliferation of smooth muscle cells and abnormal aggregation of extracellular matrix, and in situ thrombosis. It results in a gradual increase in pulmonary vascular resistance that can cause right-sided heart failure and death [1]. A recent study suggests that abnormal proliferation of PASMCs is the key pathological basis for pulmonary vascular remodeling in PAH [6] Their proliferation is promoted by vasoactive substances, such as serotonin (5-hydroxytryptamine; 5-HT) [7], which is a neurotransmitter involved in many physiological processes [8, 9]. Understanding the molecular mechanism of serotonin-induced abnormal PASMC proliferation and identifying effective therapeutic targets are key goals in PAH research
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