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.
Highlights
Coronary heart disease is a major cause of death and disability worldwide, and this disease is initiated by vascular endothelial injury
These results show that microRNA 126 (miR-126) targets PIK3R2 to inhibit endothelial progenitor cells (EPCs) endothelial-tomesenchymal transition (EndMT) and that this process involves regulation of the phosphoinositide 3-kinase (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
To investigate whether if miR-126/miR-126* host gene epidermal growth factor-like domain 7 (Egfl7) could be involved the mechanism of EndMT in EPCs, quatitative real-time PCR did not show any difference of Egfl7 mRNA expression in the presence of TGFβ1 (
Summary
Coronary heart disease is a major cause of death and disability worldwide, and this disease is initiated by vascular endothelial injury. BM-derived EPCs have the ability to transdifferentiate into a smooth muscle cell lineage positive for alpha smooth muscle actin (α-SMA), i.e., endothelial-tomesenchymal transition (EndMT) [2], suggesting a contributive role for EPCs in intimal hyperplasia during the endothelial repair process. This role was supported by published results that EPCs promote an increase in the thickness of the intimal layer in the pulmonary arteries of patients with chronic obstructive pulmonary disease [3] and that EPCs stimulate late intimal hyperplasia in porcine arteriovenous expanded polytetraflouroethylene grafts [4]. The mechanisms underlying EPC involvement in intimal hyperplasia have not yet been fully elucidated
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