Advanced glycation end products evoke endothelial cell damage by stimulating soluble dipeptidyl peptidase-4 production and its interaction with mannose 6-phosphate/insulin-like growth factor II receptor.
Advanced glycation end products evoke endothelial cell damage by stimulating soluble dipeptidyl peptidase-4 production and its interaction with mannose 6-phosphate/insulin-like growth factor II receptor.
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DOI：
10.1186/1475-2840-12-125
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发表时间：
2013-08-28
影响因子：
9.3
通讯作者：
Yamagishi S
中科院分区：
文献类型：
--
作者：
Ishibashi Y;Matsui T;Maeda S;Higashimoto Y;Yamagishi S
晚期糖基化终产物（AGEs）和受体RAGE相互作用在糖尿病血管并发症中起作用。抑制二肽基肽酶-4 （DPP-4）是2型糖尿病的潜在治疗靶点。然而，DPP-4在age诱导的内皮细胞（EC）损伤中的作用尚不清楚。在本研究中，我们研究了DPP-4对ECs中活性氧（ROS）生成和RAGE基因表达的影响。我们进一步研究了DPP-4抑制剂利格列汀是否抑制age诱导的ECs中可溶性DPP-4的产生、ROS的产生、RAGE、细胞间粘附分子-1 （ICAM-1）和纤溶酶原激活物抑制剂-1 （PAI-1）基因的表达。DPP-4剂量依赖性地增加了ECs中ROS的产生和RAGE基因的表达，而利格列汀可以阻止这一现象。甘露糖6-磷酸（M6P）和针对M6P/胰岛素样生长因子II受体（M6P/IGF-IIR）的抗体（Ab）完全阻断了DPP-4暴露的ec中ROS的产生，而表面等离子体共振显示DPP-4以3.59 × 10-5 m的解离常数与M6P/IGF-IIR结合，AGEs或过氧化氢增加了ec中可溶性DPP-4的产生，这被n-乙酰半胱氨酸、RAGE-Ab或利格列汀阻止。利格列汀显著抑制age诱导的ROS生成、RAGE、ICAM-1和PAI-1基因在ECs中的表达。本研究表明，age - rage诱导的ROS生成刺激ECs释放DPP-4， DPP-4可通过与M6P/IGF-IIR的相互作用直接作用于ECs，进一步增强AGEs的有害作用。利格列汀阻断AGE-RAGE轴与DPP-4之间的正反馈回路可能是治疗糖尿病血管损伤的新靶点。
Advanced glycation end products (AGEs) and receptor RAGE interaction play a role in diabetic vascular complications. Inhibition of dipeptidyl peptidase-4 (DPP-4) is a potential therapeutic target for type 2 diabetes. However, the role of DPP-4 in AGE-induced endothelial cell (EC) damage remains unclear. In this study, we investigated the effects of DPP-4 on reactive oxygen species (ROS) generation and RAGE gene expression in ECs. We further examined whether an inhibitor of DPP-4, linagliptin inhibited AGE-induced soluble DPP-4 production, ROS generation, RAGE, intercellular adhesion molecule-1 (ICAM-1) and plasminogen activator inhibitor-1 (PAI-1) gene expression in ECs. DPP-4 dose-dependently increased ROS generation and RAGE gene expression in ECs, which were prevented by linagliptin. Mannose 6-phosphate (M6P) and antibodies (Ab) raised against M6P/insulin-like growth factor II receptor (M6P/IGF-IIR) completely blocked the ROS generation in DPP-4-exposed ECs, whereas surface plasmon resonance revealed that DPP-4 bound to M6P/IGF-IIR at the dissociation constant of 3.59 x 10-5 M. AGEs or hydrogen peroxide increased soluble DPP-4 production by ECs, which was prevented by N-acetylcysteine, RAGE-Ab or linagliptin. Linagliptin significantly inhibited the AGE-induced ROS generation, RAGE, ICAM-1 and PAI-1 gene expression in ECs. The present study suggests that AGE-RAGE-induced ROS generation stimulates the release of DPP-4 from ECs, which could in turn act on ECs directly via the interaction with M6P/IGF-IIR, further potentiating the deleterious effects of AGEs. The blockade by linagliptin of positive feedback loop between AGE-RAGE axis and DPP-4 might be a novel therapeutic target for vascular injury in diabetes.
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DOI：
10.1073/pnas.97.15.8439
发表时间：
2000-07-18
影响因子：
11.1
作者：
Ikushima, H;Munakata, Y;Morimoto, C
通讯作者：
Morimoto, C
影响因子：
2.7
作者：
Iwaki-Egawa, S;Watanabe, Y;Fujimoto, Y
通讯作者：
Fujimoto, Y
影响因子：
4.8
作者：
Raucci, Angela;Cugusi, Simona;Bianchi, Marco E.
通讯作者：
Bianchi, Marco E.
影响因子：
2.5
作者：
Stange, T;Kettmann, U;Holzhausen, HJ
通讯作者：
Holzhausen, HJ
影响因子：
3.4
作者：
Chang, CC;Sun, W;Trosko, JE
通讯作者：
Trosko, JE