期刊
ATHEROSCLEROSIS
卷 232, 期 1, 页码 156-164出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.atherosclerosis.2013.10.025
关键词
AMPK; DAG; Endothelial cell; High glucose; Liraglutide; Metformin; Oxidative stress; PKC
资金
- Special Coordination Funds for Promoting Science and Technology (SCF funding program Innovation Center for Medical Redox Navigation)
Objective: Metformin and glucagon like peptide-1 (GLP-1) prevent diabetic cardiovascular complications and atherosclerosis. However, the direct effects on hyperglycemia-induced oxidative stress in endothelial cells are not fully understood. Thus, we aimed to evaluate the effects of metformin and a GLP-1 analog, liraglutide on high glucose-induced oxidative stress. Methods: Production of reactive oxygen species (ROS), activation of protein kinase C (PKC) and NAD(P) H oxidase, and changes in signaling molecules in response to high glucose exposure were evaluated in human aortic endothelial cells with and without treatment of metformin and liraglutide, alone or in combination. PKC-NAD(P) H oxidase pathway was assessed by translocation of GFP-fused PKC beta 2 isoform and GFP-fused p47phox, a regulatory subunit of NAD(P) H oxidase, in addition to endogenous PKC phosphorylation and NAD(P) H oxidase activity. Results: High glucose-induced ROS overproduction was blunted by metformin or liraglutide treatment, with a further decrease by a combination of these drugs. Exposure to high glucose caused PKC beta 2 translocation and a time-dependent phosphorylation of endogenous PKC but failed to induce its translocation and phosphorylation in the cells treated with metformin and liraglutide. Furthermore, both drugs inhibited p47phox translocation and NAD(P) H oxidase activation, and prevented the high glucose-induced changes in intracellulalr diacylglycerol (DAG) level and phosphorylation of AMP-activated protein kinase (AMPK). A combination of these drugs further enhanced all of these effects. Conclusions: Metformin and liraglutide ameliorate high glucose-induced oxidative stress by inhibiting PKC-NAD(P) H oxidase pathway. A combination of these two drugs provides augmented protective effects, suggesting the clinical usefulness in prevention of diabetic vascular complications. (C) 2013 Elsevier Ireland Ltd. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据