Mir-206 Regulates Pulmonary Artery Smooth Muscle Cell Proliferation and Differentiation

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.

The Roles of MicroRNAs and Protein Components of the MicroRNA Pathway in Lung Development and Diseases

“…Reduction of miR-206 in human PASMCs causes increased proliferation and reduced apoptosis, which are key histopathological features of PAH. These results suggest that miR-206 is a potential regulator of proliferation, apoptosis, and differentiation of PASMCs (135). Although the role of miR-206 in SMC proliferation has not been examined in early developing lungs, reduced expression of miR-206 by Shh might not only be responsible for the increased innervation of SMCs, but also for the promotion of SMC proliferation.…”

Molecular Mechanisms of Pulmonary Arterial Remodeling

“…Overexpression of miR-124 not only inhibited human PASMC proliferation, but also maintained its differentiated phenotype by repressing the NFAT pathway (55). It was reported that miR-206 regulates PASMC proliferation and differentiation (56) and that miR-210 has antiapoptotic effects in PASMCs during hypoxia (57). Courboulin et al reported that miR-204 plays a role in human PAH and PA remodeling (58).…”

Differential Regulation of NOTCH2 and NOTCH3 Contribute to Their Unique Functions in Vascular Smooth Muscle Cells

“…Notch signaling has also been closely associated with apoptosis and cell survival, especially in cancer cells (9, 28 -36) and smooth muscle cells (11,14,25,37,38). Notch3 specifically has been shown to promote cell survival in several different cell types (9,11,25,(33)(34)(35)37) and is a poor prognostic biomarker in several cancers (29,30,39).…”