Mierorna-138 inhibits hypoxia-induced proliferation of endothelial progenitor cells via inhibition of HIF-1[alpha]-mediated MAPK and AKT signaling

Endothelial progenitor cells (EPCs) participate in angiogenesis by differentiating into endothelial cells (ECs) and may be developed to treat ischemia/reperfusion injury. MicroRNAs (miRs) are a type of non-coding RNA that are 18-25 nucleotides in length and serve a role in angiogenesis. It has been demonstrated that miR-138 regulates hypoxia-induced EC dysfunction. However, to the best of our knowledge, the exact role of miR-138 in the regulation of hypoxia-induced EPCs has not previously been reported. In the present study, data collected from an MTT assay indicated that hypoxia treatment enhanced EPC proliferation, which was accompanied by an upregulation of hypoxia-inducible factor 1a (HIF-1a) expression. miR-138 overexpression inhibited hypoxia-induced EPC proliferation and induced cell cycle arrest at the G1 stage. A mechanistic investigation revealed that miR-138 negatively regulated HIF-1a protein levels but did not affect HIF-1a mRNA levels in EPCs. Moreover, results from a dual luciferase reporter assay demonstrated that HIF-1a was a direct target of miR-138 in EPCs. Furthermore, upregulation of miR-138 suppressed the hypoxia-induced upregulation of HIF-1a. Downstream factors of HIF-1a were also investigated and it was observed that the upregulation of miR-138 inhibited the hypoxia-induced upregulation of vascular endothelial growth factor, as well as the activity of mitogen-activated protein kinase and AKT signaling in EPCs. In summary, the present study suggested that miR-138 inhibits hypoxia-induced EPC proliferation, possibly by inhibiting HIF-1a-mediated signaling. Key words: endothelial progenitor cells, microRNA-138, proliferation, hypoxia, hypoxia-inducible factor-1[alpha]