RETRACTED ARTICLE: GLP-1 receptor agonist lixisenatide protects against high free fatty acids-induced oxidative stress and inflammatory response

Abstract

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-a, 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 IjBa activation, nuclear p65 translocation and NF-jB activation. This evidence indicates that lixisenatide suppresses activation of the NF-jB pathway in endothelial cells. Collectively, our findings suggest that lixisenatide might have therapeutic potential to modulate diabetes-associated vascular complications.

The protective effects of GLP-1 receptor agonist lixisenatide on oxygen-glucose deprivation/reperfusion (OGD/R)-induced deregulation of endothelial tube formation

“…Generation of ROS was measured by dihydroethidium (DHE) staining (****, P < 0.0001 vs. control group; ### , #### , P < 0.001, 0.0001 vs. OGD/R treatment group, n ¼ 5). Importantly, lixisenatide has shown a protective effect against free fatty acids (FFA)-induced endothelial dysfunction by suppressing the activation of the NF-kB pathway in endothelial cells, 18 which is consistent with the ndings in our study.…”

“…The cells were maintained at 37 C in a 5% CO 2 humidied incubator and used within passage 3-7 at healthy status. For pretreatment, two doses of lixisenatide (10, 20 nM) 17,18 were added to the culture media for 6 hours. For OGD/R conditioning, 95% conuent HUVECs were washed, and the culture medium was replaced with EGM media without glucose.…”

GLP-1 receptor agonists (GLP-1RAs): cardiovascular actions and therapeutic potential

“…Specifically, GLP-1RAs block NLRP3 (Nod-like receptor protein 3h) inflammasome via SIRT1 activation [111]. GLP-1RAs also suppress the nuclear factor-κB (NF-κB) pathway and free fatty acid-induced cellular ROS in endothelium [112]. GLP-1RAs also downregulate the expression of MMPs and tissue inhibitors of MPs (TIMPs) for anti-inflammation [110].…”

GLP-1 Receptor Agonists in Diabetic Kidney Disease: From Clinical Outcomes to Mechanisms

“…Liraglutide was found to increase eNOS phosphorylation and nitric oxide (NO) production via AMPK-dependent pathways in endothelial cells ( Li et al., 2016 ; Honda et al., 2018 ; Han et al., 2019 ). Lixisenatide has also been shown to prevent the free fatty acid-induced reduction of eNOS phosphorylation in endothelial cells ( Zhao et al., 2019 ). Sukumaran et al showed that liraglutide improves the renal endothelial dysfunction in obese Zucker rats on a high-salt diet by increasing the renal eNOS expression ( Sukumaran et al., 2019 ).…”