GLP-1(32-36)通过小鼠体内依赖GLP-1R的糖酵解对糖尿病缺血性下肢发挥的新型血管生成作用
Novel Angiogenesis Role of GLP-1(32-36) to Rescue Diabetic Ischemic Lower Limbs via GLP-1R-Dependent Glycolysis in Mice.
作者信息
Zhang Yikai, Wang Shengyao, Zhou Qiao, Xie Yi, Hu Yepeng, Fang Weihuan, Yang Changxin, Wang Zhe, Ye Shu, Wang Xinyi, Zheng Chao
机构信息
Department of Endocrinology, The Second Affiliated Hospital, School of Medicine (Y.Z., S.W., Q.Z., Y.X., Y.H., C.Y., Z.W., S.Y., C.Z.), Zhejiang University, Hangzhou, China.
Department of Veterinary Medicine (W.F.), Zhejiang University, Hangzhou, China.
出版信息
Arterioscler Thromb Vasc Biol. 2024 Jun;44(6):1225-1245. doi: 10.1161/ATVBAHA.124.320714. Epub 2024 Mar 21.
BACKGROUND
Restoring the capacity of endothelial progenitor cells (EPCs) to promote angiogenesis is the major therapeutic strategy of diabetic peripheral artery disease. The aim of this study was to investigate the effects of GLP-1 (glucagon-like peptide 1; 32-36)-an end product of GLP-1-on angiogenesis of EPCs and T1DM (type 1 diabetes) mice, as well as its interaction with the classical GLP-1R (GLP-1 receptor) pathway and its effect on mitochondrial metabolism.
METHODS
In in vivo experiments, we conducted streptozocin-induced type 1 diabetic mice as a murine model of unilateral hind limb ischemia to examine the therapeutic potential of GLP-1(32-36) on angiogenesis. We also generated mice to detect whether GLP-1R is required for angiogenic function of GLP-1(32-36). In in vitro experiments, EPCs isolated from the mouse bone marrow and human umbilical cord blood samples were used to detect GLP-1(32-36)-mediated angiogenic capability under high glucose treatment.
RESULTS
We demonstrated that GLP-1(32-36) did not affect insulin secretion but could significantly rescue angiogenic function and blood perfusion in ischemic limb of streptozocin-induced T1DM mice, a function similar to its parental GLP-1. We also found that GLP-1(32-36) promotes angiogenesis in EPCs exposed to high glucose. Specifically, GLP-1(32-36) has a causal role in improving fragile mitochondrial function and metabolism via the GLP-1R-mediated pathway. We further demonstrated that GLP-1(32-36) rescued diabetic ischemic lower limbs by activating the GLP-1R-dependent eNOS (endothelial NO synthase)/cGMP/PKG (protein kinase G) pathway.
CONCLUSIONS
Our study provides a novel mechanism with which GLP-1(32-36) acts in modulating metabolic reprogramming toward glycolytic flux in partnership with GLP-1R for improved angiogenesis in high glucose-exposed EPCs and T1DM murine models. We propose that GLP-1(32-36) could be used as a monotherapy or add-on therapy with existing treatments for peripheral artery disease.
REGISTRATION
URL: www.ebi.ac.uk/metabolights/; Unique identifier: MTBLS9543.
背景
恢复内皮祖细胞（EPCs）促进血管生成的能力是糖尿病外周动脉疾病的主要治疗策略。本研究旨在探讨胰高血糖素样肽1（GLP-1）的终产物GLP-1（32-36）对EPCs血管生成及1型糖尿病（T1DM）小鼠的影响，及其与经典GLP-1受体（GLP-1R）途径的相互作用和对线粒体代谢的影响。
方法
在体内实验中，我们将链脲佐菌素诱导的1型糖尿病小鼠作为单侧后肢缺血的小鼠模型，以研究GLP-1（32-36）对血管生成的治疗潜力。我们还培育了小鼠，以检测GLP-1R对于GLP-1（32-36）血管生成功能是否必需。在体外实验中，从小鼠骨髓和人脐带血样本中分离出的EPCs用于检测高糖处理下GLP-1（32-36）介导的血管生成能力。
结果
我们证明GLP-1（32-36）不影响胰岛素分泌，但能显著挽救链脲佐菌素诱导的T1DM小鼠缺血肢体的血管生成功能和血液灌注，其功能与其亲本GLP-1相似。我们还发现GLP-1（32-36）能促进高糖环境下EPCs的血管生成。具体而言，GLP-1（32-36）通过GLP-1R介导的途径在改善脆弱的线粒体功能和代谢方面具有因果作用。我们进一步证明GLP-1（32-36）通过激活GLP-1R依赖性内皮型一氧化氮合酶（eNOS）/环磷酸鸟苷（cGMP）/蛋白激酶G（PKG）途径挽救糖尿病缺血下肢。
结论
我们的研究提供了一种新机制，即GLP-1（32-36）与GLP-1R协同作用，调节代谢重编程向糖酵解通量转变，以改善高糖环境下EPCs和T1DM小鼠模型中的血管生成。我们提出GLP-1（32-36）可作为外周动脉疾病现有治疗方法的单一疗法或附加疗法。
Zotero 插件