GLP-1 receptor agonist lixisenatide protects against high free fatty acids-induced oxidative stress and inflammatory response.

Increased free fatty acids (FFA) are one of the risk factors for type 2 diabetes. FFA also contribute to endothelial dysfunction in both the prediabetes and diabetes conditions. Therefore, FFA are an important link between diabetes and endothelial dysfunction. In therapeutic application, GLP-1 receptor agonists have been implemented to lower blood glucose in diabetes. Here, we investigate the role of the common clinically used GLP-1 receptor agonist lixisenatide in endothelial cells. We demonstrate that lixisenatide could protect endothelial cells from high FFA-induced toxicity and cell death. Lixisenatide also suppresses FFA-caused cellular ROS generation and production of the lipid oxidation byproduct 4-HNE. Lixisenatide inhibits FFA-triggered production of TNF-α, IL-6, VCAM-1 and ICAM-1. The presence of lixisenatide in co-culture experiments suppresses adhesion of monocytes to endothelial cells. Moreover, lixisenatide ameliorates FFA-induced decreased eNOS phosphorylation and NO reduction. We also demonstrate that lixisenatide inhibits FFA-induced IκBα activation, nuclear p65 translocation and NF-κB activation. This evidence indicates that lixisenatide suppresses activation of the NF-κB pathway in endothelial cells. Collectively, our findings suggest that lixisenatide might have therapeutic potential to modulate diabetes-associated vascular complications.