microRNA 126 Inhibits the Transition of Endothelial Progenitor Cells to Mesenchymal Cells via the PIK3R2-PI3K/Akt Signalling Pathway

Abstract

AimsEndothelial progenitor cells (EPCs) are capable of proliferating and differentiating into mature endothelial cells, and they have been considered as potential candidates for coronary heart disease therapy. However, the transition of EPCs to mesenchymal cells is not fully understood. This study aimed to explore the role of microRNA 126 (miR-126) in the endothelial-to-mesenchymal transition (EndMT) induced by transforming growth factor beta 1 (TGFβ1). Methods and ResultsEndMT of rat bone marrow-derived EPCs was induced by TGFβ1 (5 ng/mL) for 7 days. miR-126 expression was depressed in the process of EPC EndMT. The luciferase reporter assay showed that the PI3K regulatory subunit p85 beta (PIK3R2) was a direct target of miR-126 in EPCs. Overexpression of miR-126 by a lentiviral vector (lenti-miR-126) was found to downregulate the mRNA expression of mesenchymal cell markers (α-SMA, sm22-a, and myocardin) and to maintain the mRNA expression of progenitor cell markers (CD34, CD133). In the cellular process of EndMT, there was an increase in the protein expression of PIK3R2 and the nuclear transcription factors FoxO3 and Smad4; PI3K and phosphor-Akt expression decreased, a change that was reversed markedly by overexpression of miR-126. Furthermore, knockdown of PIK3R2 gene expression level showed reversed morphological changes of the EPCs treated with TGFβ1, thereby giving the evidence that PIK3R2 is the target gene of miR-126 during EndMT process. ConclusionsThese results show that miR-126 targets PIK3R2 to inhibit EPC EndMT and that this process involves regulation of the PI3K/Akt signalling pathway. miR-126 has the potential to be used as a biomarker for the early diagnosis of intimal hyperplasia in cardiovascular disease and can even be a therapeutic tool for treating cardiovascular diseases mediated by the EndMT process.

Micro RNA-126 coordinates cell behavior and signaling cascades according to characteristics of breast cancer cells

“…Over stimulation of endothelial cells with VEGF leads to hyperactivity of the receptor (VEGFR 2 ). In cancer cells, (15,21,40). While SPRED-1 inhibits the activation of MAPK signaling, PIK 3 R 2 is associated with the inhibition of VEGF/PI3K/ AKT signaling (15,20).…”

“…Therefore, molecules altering the expression of PIK 3 R 2 may be an effective way to lower the malignancy of cancer types. Several previous reports have demonstrated that miR-126 reduces the expression of PIK 3 R 2 by directly targeting its 3'-untranslated region (20,21).…”

FGF2 inhibits endothelial–mesenchymal transition through microRNA-20a-mediated repression of canonical TGF-β signaling

“…*P<0.05; **P<0.01; ***P<0.001 (one-way ANOVA followed by Bonferroni post-tests). MicroRNAs are involved in EndMT (Bijkerk et al, 2012;Fang and Davies, 2012;Ghosh et al, 2012;Kumarswamy et al, 2012;Zhang et al, 2013) and fibroproliferative diseases (Thum et al, 2008;van Rooij et al, 2008;Kato et al, 2009;Chung et al, 2010) by targeting genes that are crucial for endothelial homeostasis or activating fibroblasts. However, the role of microRNAs that are lost during EndMT and fibroproliferative diseases remains elusive.…”

A Stromal Cell-Derived Factor 1α Analogue Improves Endothelial Cell Function in Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome

“…It has previously been shown to have pleiotropic effects during EC differentiation and its genetic absence is known to augment vascular permeability (22,31). A potential mechanism by which miR-126 may decrease vascular permeability includes its targeted inhibition of PIK3R2 (32). PIK3R2 suppresses AKT signaling (32,33), which has been shown to play a critical role in modulating cytoskeletal rearrangement and maintaining barrier integrity (34).…”

“…A potential mechanism by which miR-126 may decrease vascular permeability includes its targeted inhibition of PIK3R2 (32). PIK3R2 suppresses AKT signaling (32,33), which has been shown to play a critical role in modulating cytoskeletal rearrangement and maintaining barrier integrity (34). Thus, increases in miR-126 levels may be expected to augment AKT signaling and enhance vascular barrier integrity while its absence would generate the Figure 5.…”