Retraction of "GPR40 Agonist GW9508 Ameliorates Oxidized LDL-Induced Endothelial Dysfunction via the AMPK/CREB/PGC-1α Pathway".

Abstract

Oxidized low-density lipoprotein (ox-LDL)-induced endothelial dysfunction has been recognized as an important early event in atherosclerosis. G-protein-coupled receptor 40 (GPR40) is a cell surface receptor that is highly expressed in endothelial cells. The physiological function of GPR40 in endothelial cells remains to be elucidated. In this study, we found that ox-LDL stimulation reduced the expression of GPR40 in a dose-dependent manner from 50 to 150 μg/ml in human aortic endothelial cells (HAECs). Interestingly, we found that the activation of GPR40 by its agonist GW9508 ameliorated ox-LDL-induced reduced cell viability of HAECs. Furthermore, our results indicate that GW9508 treatment improved mitochondrial function by restoring ox-LDL-induced reduced mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) production. Mechanistically, we found that GW9508 mitigated ox-LDL-induced inactivation of adenosine 5'-monophosphate (AMP)-activated protein kinase α (AMPKα), however, the blockage of GPR40 by its antagonist GW1100 completely abolished the protective effect of GW9508 on AMPKα activation. Importantly, treatment with the AMPKα inhibitor compound C abolished the beneficial effects of GW9508 on NADPH oxidase activity, cellular reactive oxygen species (ROS) production, and superoxide dismutase (SOD) activity, suggesting that the cellular protective effects of GW9508 are mediated by AMPKα. Additionally, GW9508 also restored ox-LDL-induced dephosphorylation of cAMP-responsive element-binding protein (CREB), which was also abolished by compound C. Finally, we found that AMPKα and CREB participated in mediating the effects of GW9508 on the expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and mitochondrial homeostasis. These findings suggest that GW9508 possesses an important protective effect in endothelial cells against ox-LDL-induced damages.