Ipt preparation. HC designed the study and participated in data analysis and interpretation, and manuscript preparation. All authors have read and approved the final version of the manuscript.AcknowledgementsThe authors’ work is supported by National Heart, Lung and Blood Institute Grants HL-077440, HL-081571, an American Heart Association Grant SKF-96365 (hydrochloride) site 0435189N, an American Diabetes Association Award 7-04-RA-16, a Career PamapimodMedChemExpress Pamapimod Development Award from the Schweppe Foundation, and start-up funds from the University of Chicago and University of California Los Angeles (all to H. Cai).
Ishibashi et al. Cardiovascular Diabetology 2013, 12:125 http://www.cardiab.com/content/12/1/CARDIO VASCULAR DIABETOLOGYORIGINAL INVESTIGATIONOpen AccessAdvanced glycation end products evoke endothelial cell damage by stimulating soluble dipeptidyl peptidase-4 production and its interaction with mannose 6-phosphate/insulinlike growth factor II receptorYuji Ishibashi1, Takanori Matsui1, Sayaka Maeda1, Yuichiro Higashimoto2 and Sho-ichi Yamagishi1*AbstractBackground: 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. Keywords: AGEs, RAGE, DPP-4, Mannose 6-phosphate/IGF-II receptor* Correspondence: [email protected] 1 Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan Full list of author information is available at the end of the article?2013 Ishibashi et PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/27362935 al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Ishibashi et al. Car.Ipt preparation. HC designed the study and participated in data analysis and interpretation, and manuscript preparation. All authors have read and approved the final version of the manuscript.AcknowledgementsThe authors’ work is supported by National Heart, Lung and Blood Institute Grants HL-077440, HL-081571, an American Heart Association Grant 0435189N, an American Diabetes Association Award 7-04-RA-16, a Career Development Award from the Schweppe Foundation, and start-up funds from the University of Chicago and University of California Los Angeles (all to H. Cai).
Ishibashi et al. Cardiovascular Diabetology 2013, 12:125 http://www.cardiab.com/content/12/1/CARDIO VASCULAR DIABETOLOGYORIGINAL INVESTIGATIONOpen AccessAdvanced glycation end products evoke endothelial cell damage by stimulating soluble dipeptidyl peptidase-4 production and its interaction with mannose 6-phosphate/insulinlike growth factor II receptorYuji Ishibashi1, Takanori Matsui1, Sayaka Maeda1, Yuichiro Higashimoto2 and Sho-ichi Yamagishi1*AbstractBackground: 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. Keywords: AGEs, RAGE, DPP-4, Mannose 6-phosphate/IGF-II receptor* Correspondence: [email protected] 1 Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan Full list of author information is available at the end of the article?2013 Ishibashi et PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/27362935 al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Ishibashi et al. Car.
