Abstract
Pulmonary Arterial Hypertension (PAH) is a progressive devastating disease characterized by excessive proliferation of the Pulmonary Arterial Smooth Muscle Cells (PASMCs). Studies suggest that PAH and cancers share an apoptosis-resistant state featuring excessive cell proliferation. MicroRNA-206 (miR-206) is known to regulate proliferation and is implicated in various types of cancers. However, the role of miR-206 in PAH has not been studied. In this study, it is hypothesized that miR-206 could play a role in the proliferation of PASMCs. In the present study, the expression patterns of miR-206 were investigated in normal and hypertensive mouse PASMCs. The effects of miR-206 in modulating cell proliferation, apoptosis and smooth muscle cell markers in human pulmonary artery smooth muscle cells (hPASMCs) were investigated in vitro. miR-206 expression in mouse PASMCs was correlated with an increase in right ventricular systolic pressure. Reduction of miR-206 levels in hPASMCs causes increased proliferation and reduced apoptosis and these effects were reversed by the overexpression of miR-206. miR-206 over expression also increased the levels of smooth muscle cell differentiation markers α-smooth muscle actin and calponin implicating its importance in the differentiation of SMCs. miR-206 overexpression down regulated Notch-3 expression, which is key a factor in PAH development. These results suggest that miR-206 is a potential regulator of proliferation, apoptosis and differentiation of PASMCs, and that it could be used as a novel treatment strategy in PAH.
Highlights
Pulmonary arterial hypertension (PAH) is a disease characterized by a progressive increase in pulmonary vascular resistance, causing an increase in pulmonary artery blood pressure [1] leading to right heart failure and death
We report for the first time that over expression of miR-206 decreases proliferation, increases apoptosis and induces smooth muscle cell differentiation markers (a-Smooth Muscle Actin (SMA) and calponin) expression in human pulmonary artery smooth muscle cells (PASMCs). miR-206 inhibits Notch3 protein expression levels and providing an explanation for increased Notch-3 levels in PAH
MiR-206 Over Expression Decreases Proliferation in human pulmonary artery smooth muscle cells (hPASMCs) miR-206 expression levels were found to be significantly lower in mice with pulmonary hypertension induced by hypoxia as compared to normoxic mice and suggest that miR-206 may play a role in regulating the proliferative phenotype of the pulmonary vasculature
Summary
Pulmonary arterial hypertension (PAH) is a disease characterized by a progressive increase in pulmonary vascular resistance, causing an increase in pulmonary artery blood pressure [1] leading to right heart failure and death Both pulmonary artery smooth muscle cells (PASMCs) and pulmonary artery endothelial cells (PAECs) are affected by this disease. In vivo experiments showed lower expression of miR-206 in hypoxia induced PAH mice when compared to control mice (Room air) Based on this evidence, the effects of miR-206 in modulating cell proliferation, apoptosis of PASMCs in vitro, and miR-2069s role in affecting PASMCs differentiation were investigated. We report for the first time that over expression of miR-206 decreases proliferation, increases apoptosis and induces smooth muscle cell differentiation markers (a-SMA and calponin) expression in human PASMCs. miR-206 inhibits Notch protein expression levels and providing an explanation for increased Notch-3 levels in PAH
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