The GLP-1 receptor agonist liraglutide protects against oxidized LDL-induced endothelial inflammation and dysfunction via KLF2

Cardiovascular complications are the major causes of the mortality and morbidities in diabetic patients. The diabetic patients have an increased risk of developing atherosclerosis, which could lead to heart attack and stroke. Glucagon-like peptide 1 (GLP-1) receptor agonists are a class of potent anti-glycemic agents to treat diabetes. Recently, several GLP-1 receptor agonists have been found to have cardiovascular benefit independent of their glucose lowing ability. Liraglutide is one of clinically approved effective GLP-1 receptor agonists. In this study, we explored the molecular mechanism of Liraglutide against oxidized low-density lipoprotein (ox-LDL) in cultured endothelial cells. Our data show that Liraglutide treatment ameliorates ox-LDL caused reduction of the transcriptional factor KLF2. In the same experiment, Liraglutide also rescues ox-LDL induced reduction of mitogen-activated protein kinase (MAPK) kinase extracellular signal regulated kinase 5 (ERK5) phosphorylation, and blockage of ERK5 activity by its inhibitor XMD8-92 abolishes the protection of Liraglutide on KLF2 expression. These facts suggest that the action of Liraglutide on endothelial KLF2 is dependent on ERK5. Liraglutide also recovers ox-LDL caused reduction of endothelial tight junctions protein Occludin and ameliorates ox-LDL induced endothelial monolayer permeability increase. On the other hand, Liraglutide inhibits ox-LDL induced expression of vascular adhesion molecules (E-selectin and vascular cell adhesion molecule 1), and prevents ox-LDL induced attachment of monocytes adhesion to endothelial cells. Moreover, Liraglutide mitigates ox-LDL triggered reduction of endothelial nitric oxide synthase (eNOS) expression and NO release. Collectively, our study provides multiple facets of the mechanisms that Liraglutide is a protective agent in endothelial cells and has the potential implication in therapeutic usage of vascular complication in diabetes patients. (c) 2019 IUBMB Life, 71(9):1347-1354, 2019