DPP4 inhibitors promote biological functions of human endothelial progenitor cells by targeting the SDF-1/CXCR4 signaling pathway

Abstract

Dipeptidyl peptidase 4 (DPP4) inhibitors (oral hypoglycemic agents) have beneficial effects during the early stages of diabetes. In this study, we evaluated the role of DPP4 inhibitors on the biological functions of cultured human endothelial progenitor cells (EPCs). After treating EPCs with the DPP4 inhibitors sitagliptin and vildagliptin, we examined the mRNA expression of DPP4, vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR-2), endothelial nitric oxide synthase (eNOS), caspase-3, stromal cell-derived factor-1 (SDF-1), chemokine (C-X-C motif) receptor 4 (CXCR4) were measured by RT-PCR. The protein expression of SDF-1 and CXCR4 was determined by Western blot; cell proliferation was tested by the MTT method, and DPP4 activity was determined by a DPP4 assay. Our results revealed that DPP4 expression and activity were inhibited following the treatment with various doses of DPP4 inhibitors. Cell proliferation and the expression of VEGF, VEGFR-2 and eNOS were upregulated, while cell apoptosis was inhibited by DPP4 inhibitors in a dose-dependent manner. DPP4 inhibitors activated the SDF-1/CXCR4 signaling pathway, shown by the elevated expression of SDF-1/CXCR4. This further proved that after the SDF-1/CXCR4 signaling pathway was blocked by its inhibitor ADM3100, the effects of DPP4 inhibitors on the proliferation and apoptosis, and the expression of VEGF, VEGFR-2 and eNOS of EPCs were significantly reduced. These findings suggest that DPP4 inhibitors promote the biological functions of human EPCs by upregulating the SDF-1/CXCR4 signaling pathway.