Liraglutide prevents high glucose induced HUVECs dysfunction via inhibition of PINK1/Parkin-dependent mitophagy

Functional loss of endothelial cells will lead to development and progression of atherosclerosis in diabetic patients. However, dysfunction of endothelial cells in diabetes has yet to be fully understood. We aimed to characterize the potential effects of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, on preventing high glucose-induced endothelial dysfunction and excessive mitophagic response. Pretreatment with liraglutide prevented downregulation of eNOS phosphorylation and NO secretion, and reduced apoptosis and oxidative stress of the human umbilical vein endothelial cells (HUVECs) exposed to high glucose. We further demonstrated that liraglutide likely mediated such protective effects by reducing PINK1/Parkin mediated mitophagy. Liraglutide markedly decreased high glucose-induced mitochondrial ROS, lessened PINK1 expression and mitochondrial accumulation of Parkin, but recovered SIRT1 expression. Seahorse analysis revealed that liraglutide mitigated high glucose-induced reduction of basal and maximum respiration rates as well as spare respiration capacity. Inhibition of Parkin by RNA silencing not only resulted in increased mitochondrial and cytosolic ROS and reduced mitochondrial mass and mitochondrial membrane potential, but also led to increased apoptotic responses in high glucose treated HUVECs which were not preventable by liraglutide. Together, our study reveals that liraglutide acts upstream of the PINK1/Parkin pathway to effectively counteract high glucose induced cell dysfunction by suppression of the PINK1/Parkin-dependent mitophagy. Therefore, its use as an adjunct therapy for type 2 diabetes mellitus is warranted to reduce the risk of atherosclerosis. Further research is required to examine the exact molecules, including SIRT1, upstream of the PINK1/parkin pathway that liraglutide targets to maintain the mitochondrial homeostasis. • Liraglutide improved functionality of HUVECs perturbed by high glucose. • Mitochondrial damage was related to high-glucose exposure which could be preventable by liraglutide. • Liraglutide rescues high glucose-induced PINK1/Parkin-dependent mitophagy. • Liraglutide modulate mitochondrial homeostasis and mitophagic response upstream of PINK1-Parkin pathway.