Exendin-4 reverses high glucose-induced endothelial progenitor cell dysfunction via SDF-1β/CXCR7-AMPK/p38-MAPK/IL-6 axis

Abstract

Aim: Exendin-4, a glucagon-like peptide-1 (GLP-1) analog, has been used for treating diabetes mellitus (DM). However, its effects on improving the dysfunction of high glucose (HG)-induced endothelial progenitor cells (EPCs) remain unclear. The present study explored the effects of Exendin-4 on improving dysfunction of EPCs and the underlying mechanism.

Methods: EPCs were isolated from SD rats and identified by flow cytometry. Next, the EPCs were treated by HG and high or low concentration of Exendin-4, and cell viability, migration and tube formation were, respectively, examined by performing MTT assay, wound-healing assay and tube formation assay. Interleukin-6 (IL-6) secretion was measured by enzyme-linked immunosorbent assay (ELISA). The protein expressions of relative stromal-derived growth factor-1β (SDF-1β), C-X-C chemokine receptor type 7 (CXCR7), AMP-activated protein kinase (AMPK), p38 and expressions of CXCR7 and IL-6 in EPCs were measured by Western blot. The cell behaviors of EPCs treated by HG and Exendin-4 with or without silencing of CXCR7 and IL-6 were detected.

Results: Exendin-4 reversed the inhibitory effects of HG on viability, migration and tube formation of EPCs and on SDF-1β/CXCR7-AMPK pathway in EPCs in a dose-dependent manner. Moreover, Exendin-4 promoted the effects of HG on IL-6 level in EPCs through the promotion of p38-MAPK phosphorylation and reduction of cleaved caspase-3 protein expressions in EPCs. However, silencing of CXCR7 and IL-6 reversed the effects of Exendin-4 on cell behaviors, inactivated SDF-1β/CXCR7-AMPK pathway and increased cleaved caspase-3 expression in EPCs.

Conclusions: Exendin-4 could ameliorate HG-induced EPC dysfunction through regulating the production of IL-6 via SDF-1β/CXCR7-AMPK/p38-MAPK axis.

Keywords: Diabetes mellitus; Endothelial progenitor cell dysfunction; Exendin-4; Interleukin-6; SDF-1β/CXCR7–AMPK/p38-MAPK axis.