A GLP-1 receptor agonist liraglutide inhibits endothelial cell dysfunction and vascular adhesion molecule expression in an ApoE-/- mouse model
A GLP-1 receptor agonist liraglutide inhibits endothelial cell dysfunction and vascular adhesion molecule expression in an ApoE-/- mouse model
复制标题
DOI：
10.1177/1479164111404257
复制
发表时间：
2011-04-01
影响因子：
2.4
通讯作者：
Dear, Anthony E.
中科院分区：
文献类型：
--
作者：
Gaspari, Tracey;Liu, HongBin;Dear, Anthony E.
胰高血糖素样肽 1 受体 (GLP-1R) 激动剂利拉鲁肽可在体外减弱人血管内皮细胞 (hVEC) 中 1 型纤溶酶原激活剂抑制剂 (PAI-1) 和血管粘附分子 (YAM) 表达的诱导，并可能针对内皮细胞功能障碍 (ECD)（糖尿病血管疾病的早期异常）提供保护。我们的研究旨在确定利拉鲁肽体外效应对 GLP-1R 的依赖性，并表征其在 ECD 小鼠模型中的体内效应。体外研究利用人血管内皮细胞系C1 1-STH和酶联免疫吸附测定(ELISA)来测定PAI-I和YAM表达。在 ApoE(-/-) 小鼠模型中进行了血管反应性和免疫组织化学分析的体内研究。体外研究表明 GLP-1R 依赖性利拉鲁肽介导的对受刺激的 PAI-1 和 YAM 表达的抑制。体内研究表明，利拉鲁肽治疗小鼠的内皮功能显着改善，这是一种 GLP-1R 依赖性效应。利拉鲁肽治疗还增加了主动脉内皮细胞内皮一氧化氮合酶 (eNOS) 的表达并减少了细胞间粘附分子 1 (ICAM-1) 的表达，这一作用再次依赖于 GLP-1R。这些研究共同确定了 GLP-1R 激动剂利拉鲁肽针对 ECD 的体内保护作用，并提供了导致这些作用的潜在分子机制。
The glucagon like peptide-1 receptor (GLP-1R) agonist liraglutide attenuates induction of plasminogen activator inhibitor type-1 (PAI-1) and vascular adhesion molecule (YAM) expression in human vascular endothelial cells (hVECs) in vitro and may afford protection against endothelial cell dysfunction (ECD), an early abnormality in diabetic vascular disease. Our study aimed to establish the dependence of the in vitro effects of liraglutide on the GLP-1R and characterise its in vivo effects in a mouse model of ECD. In vitro studies utilised the human vascular endothelial cell line C1 1-STH and enzyme-linked immunosorbent assays (ELISA) for determination of PAI-I and YAM expression. In vivo studies of vascular reactivity and immunohistochemical analysis were performed in the ApoE(-/-) mouse model. In vitro studies demonstrated GLP-1R-dependent liraglutide-mediated inhibition of stimulated PAI-1 and YAM expression. In vivo studies demonstrated significant improvement in endothelial function in liraglutide treated mice, a GLP-1R dependent effect. Liraglutide treatment also increased endothelial nitric oxide synthase (eNOS) and reduced intercellular adhesion molecule-1 (ICAM-1) expression in aortic endothelium, an effect again dependent on the GLP-1R. Together these studies identify in vivo protection, by the GLP-1R agonist liraglutide, against ECD and provide a potential molecular mechanism responsible for these effects.