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.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Yuji Ishibashi, Takanori Matsui, Sayaka Maeda, Yuichiro Higashimoto, Sho-ichi Yamagishi
• Journal: Cardiovascular diabetology (Cardiovasc Diabetol) Vol. 12 Pg. 125 (Aug 28 2013) ISSN: 1475-2840 [Electronic] England
• PMID: 23984879 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dipeptidyl-Peptidase IV Inhibitors
• Glycation End Products, Advanced
• ICAM1 protein, human
• Plasminogen Activator Inhibitor 1
• Reactive Oxygen Species
• Receptor for Advanced Glycation End Products
• Receptor, IGF Type 2
• Receptors, Immunologic
• SERPINE1 protein, human
• cation-dependent mannose-6-phosphate receptor
• Intercellular Adhesion Molecule-1
• DPP4 protein, human
• Dipeptidyl Peptidase 4

Topics

• Cells, Cultured
• Dipeptidyl Peptidase 4 (metabolism)
• Dipeptidyl-Peptidase IV Inhibitors (pharmacology)
• Dose-Response Relationship, Drug
• Glycation End Products, Advanced (metabolism)
• Human Umbilical Vein Endothelial Cells (drug effects, enzymology, pathology)
• Humans
• Intercellular Adhesion Molecule-1 (genetics, metabolism)
• Oxidative Stress
• Paracrine Communication
• Plasminogen Activator Inhibitor 1 (genetics, metabolism)
• Reactive Oxygen Species (metabolism)
• Receptor for Advanced Glycation End Products
• Receptor, IGF Type 2 (metabolism)
• Receptors, Immunologic (genetics, metabolism)
• Signal Transduction
• Time Factors
• Up-Regulation