Involvement of Vascular Endothelial Cells in the Anti-atherogenic Effects of Liraglutide in Diabetic Apolipoprotein E-null Mice

抄録

Glucagon-like peptide 1 receptor agonists （GLP-1RAs） have been shown to exert anti-atherosclerotic effects via multiple mechanisms on different types of cells. However, it is unclear which of these mechanisms are crucial. We investigated the role of vascular endothelial cells （VECs） in the anti-atherogenic effects of the GLP-1RA liraglutide in a mouse model of atherosclerosis. Streptozotocin-induced diabetic apolipoprotein E-null mice were randomly assigned to treatment with either vehicle （saline） or liraglutide （107nmol/kg/day）, and were subjected to femoral artery wire injury to remove VECs. After 4 weeks, vessel samples were collected for analysis. Streptozotocin-injected mice had fasting plasma glucose levels of ＞300mg/dl and hemoglobin A1c levels of ＞9％, indicating that the injections had induced severe hyperglycemia. However, there were no differences in metabolic characteristics such as levels of hemoglobin A1c, fasting plasma glucose, total cholesterol, and triglycerides between the vehicle and liraglutide groups. Analysis of atherosclerotic plaque formation revealed that liraglutide treatment significantly suppressed plaque formation in the aorta. In addition, liraglutide treatment reduced plaque volume and intra-plaque macrophage accumulation at the aortic sinus. Furthermore, liraglutide treatment suppressed vascular expression of pro-inflammatory cytokines. In uninjured femoral arteries, no plaques were observed; however, severe plaque formation occurred in femoral arteries that had been injured by wire insertion to remove VECs. Unlike in the uninjured aorta, liraglutide treatment did not affect plaque volume or arterial remodeling （intimal and medial thinning, and arterial dilation） in wire-injured femoral arteries. Of the various cells that liraglutide affects, VECs play a central role in liraglutide’s anti-atherogenic effects in diabetic mice.