Inhibition of microRNA-139-5p by glucagon-like peptide-1 ameliorates oxidative stress-induced vascular endothelial cell damage via targeting SOD1/GCLc.

Abstract

Graphical abstract:

Abstract: Oxidative stress is a key driving factor for the progression of vascular disease in diabetes, and is closely related to endothelial dysfunction. The exact mechanism by which glucagon-like peptide-1 (GLP-1) directly protects vascular endothelium by reducing oxidative stress is not yet fully understood. In this study, we investigated the protective effect of GLP-1 on endothelial cells exposed to palmitic acid (PA)/high glucose-induced oxidative stress and further explored the potential mechanisms involved in microRNA-139-5p (miR-139-5p) regulation. We found that miR-139-5p expression was exhibited significantly elevated in HUVECs that were exposed to PA/high glucose or H2O2, which were reversed by glutathione. Interestingly, this expression was significantly attenuated after GLP-1 pretreatment, with reduced reactive oxygen species (ROS), increased GSH/GSSG ratio and amelioration of cell dysfunction. Overexpression of miR-139-5p resulted in increased ROS and apoptosis, decreased GSH/GSSG ratio, damaged migration and proliferation of HUVECs, while inhibition of miR-139-5p significantly restored PA-induced HUVECs impairments. Further investigation revealed that miR-139-5p directly targets superoxide dismutase 1 (SOD1)/glutamate-cysteine ligase catalytic (GCLc) subunit. The upregulation of miR-139-5p abrogated the protective effects of GLP-1 on cells exposed to PA, and GLP-1-induced downregulation of miR-139-5p was counteracted by the GLP-1 receptor antagonist exendin(9-39). These findings demonstrated that GLP-1 ameliorates oxidative stress-induced endothelial dysfunction, at least in part, by suppressing miR-139-5p, which targets SOD1 and GCLc. This provides further evidence for the vascular protective effects of GLP-1 intervention in diabetes.