Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan.
Cardiovasc Diabetol. 2013 Aug 28;12:125. doi: 10.1186/1475-2840-12-125.
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.
晚期糖基化终产物（AGEs）与受体 RAGE 的相互作用在糖尿病血管并发症中发挥作用。二肽基肽酶-4（DPP-4）的抑制可能是 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。
在这项研究中，我们研究了 DPP-4 对 EC 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 linagliptin 是否抑制 AGE 诱导的可溶性 DPP-4 产生、ROS 生成、RAGE、细胞间黏附分子-1（ICAM-1）和纤溶酶原激活物抑制剂-1（PAI-1）在 EC 中的基因表达。
DPP-4 以剂量依赖性方式增加 EC 中的 ROS 生成和 RAGE 基因表达，linagliptin 可预防这种作用。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）的抗体完全阻断了 DPP-4 暴露的 EC 中的 ROS 生成，而表面等离子体共振显示 DPP-4 以 3.59 x 10⁻⁵ M 的解离常数与 M6P/IGF-IIR 结合。AGE 或过氧化氢增加了 EC 中可溶性 DPP-4 的产生，N-乙酰半胱氨酸、RAGE-Ab 或 linagliptin 可预防这种作用。Linagliptin 显著抑制了 AGE 诱导的 EC 中 ROS 生成、RAGE、ICAM-1 和 PAI-1 基因表达。
本研究表明，AGE-RAGE 诱导的 ROS 生成刺激 EC 释放 DPP-4，DPP-4 可通过与 M6P/IGF-IIR 的相互作用直接作用于 EC，进一步增强 AGE 的有害作用。通过 linagliptin 阻断 AGE-RAGE 轴与 DPP-4 之间的正反馈环可能是糖尿病血管损伤的新治疗靶点。
