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Open Access Original investigation

Advanced glycation end products potentiate citrated plasma-evoked oxidative and inflammatory reactions in endothelial cells by up-regulating protease-activated receptor-1 expression

Yuji Ishibashi1, Takanori Matsui1, Seiji Ueda2, Kei Fukami2 and Sho-ichi Yamagishi1*

Author Affiliations

1 Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan

2 Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan

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Cardiovascular Diabetology 2014, 13:60  doi:10.1186/1475-2840-13-60

Published: 13 March 2014

Abstract

Advanced glycation end products (AGEs) and receptor RAGE interaction contribute to endothelial cell damage in diabetes. Several thrombogenic abnormalities are also involved in diabetic vascular complications. However, the pathological role of thrombin and protease-activated receptor-1 (PAR-1) system in AGE-induced endothelial cell (EC) damage remains unclear. In this study, we investigated the effects of rivaroxaban, an inhibitor of factor Xa on 3% citrated human plasma-evoked reactive oxygen species (ROS) generation and RAGE, monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule-1 (ICAM-1) gene expression in AGE-exposed ECs. We further examined whether FR171113, an inhibitor of PAR-1 blocked the plasma-induced EC damage and if AGEs increased PAR-1 expression in ECs. Human citrated plasma stimulated ROS generation and RAGE, MCP-1 and ICAM-1 expression in ECs, all of which were potentiated by the treatment with AGEs. Rivaroxaban or FR171113 significantly inhibited these derangements in plasma- or plasma plus AGE-exposed ECs. Moreover, AGEs significantly increased the PAR-1 levels in ECs. The present study suggests that citrated plasma could induce oxidative and inflammatory reactions in ECs via the activation of thrombin-PAR-1 system and that AGEs could potentiate the plasma-evoked EC damages via up-regulation of PAR-1. Blockade of the crosstalk between AGE-RAGE axis and coagulation system by rivaroxaban might be a novel therapeutic target for thromboembolic disorders in diabetes.

Keywords:
AGEs; RAGE; Endothelial cells; Diabetes; PAR-1; Rivaroxaban