Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo, 142-8501, Japan.
Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo, 142-8501, Japan.
Eur J Pharmacol. 2019 Dec 15;865:172776. doi: 10.1016/j.ejphar.2019.172776. Epub 2019 Nov 4.
The incretin glucagon-like peptide-1 (GLP-1) elicits direct favorable effects on the cardiovascular system. This study aimed to evaluate the acute effects of GLP-1 on improving aortic endothelial dysfunction in diabetic mice. Additionally, we examined whether GLP-1 elucidated the underlying mechanisms. Using the diabetic mouse models induced by nicotinamide and streptozotocin, we investigated the functional changes in the aorta caused by GLP-1. Organ baths were performed for vascular reactivity in isolated aortic rings, and western blotting was used for protein analysis. The diabetic aortas showed enhanced GLP-1-induced relaxation response and nitric oxide (NO) production. However, the pretreatment of GLP-1 did not significantly change the endothelial-dependent relaxation response to acetylcholine and -independent relaxation response to sodium nitroprusside. On the other hand, the GLP-1-induced relaxation response and NO production were abolished by the endothelial NO synthase inhibitor, GLP-1 receptor antagonist, Akt inhibitor, and AMP-activated protein kinase (AMPK) inhibitor. Finally, in diabetic mice, considerable increases in phosphorylation of Akt and AMPK were found in aortas stimulated with GLP-1, both of which were decreased by pretreatment with the AMPK inhibitor. GLP-1 significantly enhanced endothelial-dependent relaxation in diabetic aortas. The effect may be mediated through activation of the AMPK/Akt pathway via a GLP-1 receptor-dependent mechanism.
胰高血糖素样肽-1（GLP-1）可直接对心血管系统产生有利影响。本研究旨在评估 GLP-1 对改善糖尿病小鼠主动脉内皮功能障碍的急性作用。此外，我们还研究了 GLP-1 是否阐明了潜在的机制。我们使用烟酰胺和链脲佐菌素诱导的糖尿病小鼠模型，研究了 GLP-1 引起的主动脉功能变化。使用离体主动脉环进行血管反应性器官浴实验，并进行蛋白质分析的 Western 印迹。糖尿病主动脉显示出增强的 GLP-1 诱导的松弛反应和一氧化氮（NO）产生。然而，GLP-1 的预处理并没有显著改变乙酰胆碱引起的内皮依赖性松弛反应和硝普钠引起的非依赖性松弛反应。另一方面，GLP-1 诱导的松弛反应和 NO 产生被内皮型一氧化氮合酶抑制剂、GLP-1 受体拮抗剂、Akt 抑制剂和 AMP 激活蛋白激酶（AMPK）抑制剂所抑制。最后，在糖尿病小鼠中，GLP-1 刺激的主动脉中发现 Akt 和 AMPK 的磷酸化显著增加，而 AMPK 抑制剂预处理可降低磷酸化。GLP-1 可显著增强糖尿病主动脉的内皮依赖性松弛。该作用可能是通过 GLP-1 受体依赖性机制，通过激活 AMPK/Akt 通路介导的。
