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Dipeptidyl Peptidase‐4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation

BACKGROUND: Chronic inflammation plays a key role in the pathogenesis of intracranial aneurysms (IAs). DPP‐4 (dipeptidyl peptidase‐4) inhibitors have anti‐inflammatory effects, including suppressing macrophage infiltration, in various inflammatory models. We examined whether a DPP‐4 inhibitor, anagl...

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Autores principales: Ikedo, Taichi, Minami, Manabu, Kataoka, Hiroharu, Hayashi, Kosuke, Nagata, Manabu, Fujikawa, Risako, Higuchi, Sei, Yasui, Mika, Aoki, Tomohiro, Fukuda, Miyuki, Yokode, Masayuki, Miyamoto, Susumu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669147/
https://www.ncbi.nlm.nih.gov/pubmed/28630262
http://dx.doi.org/10.1161/JAHA.116.004777
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author Ikedo, Taichi
Minami, Manabu
Kataoka, Hiroharu
Hayashi, Kosuke
Nagata, Manabu
Fujikawa, Risako
Higuchi, Sei
Yasui, Mika
Aoki, Tomohiro
Fukuda, Miyuki
Yokode, Masayuki
Miyamoto, Susumu
author_facet Ikedo, Taichi
Minami, Manabu
Kataoka, Hiroharu
Hayashi, Kosuke
Nagata, Manabu
Fujikawa, Risako
Higuchi, Sei
Yasui, Mika
Aoki, Tomohiro
Fukuda, Miyuki
Yokode, Masayuki
Miyamoto, Susumu
author_sort Ikedo, Taichi
collection PubMed
description BACKGROUND: Chronic inflammation plays a key role in the pathogenesis of intracranial aneurysms (IAs). DPP‐4 (dipeptidyl peptidase‐4) inhibitors have anti‐inflammatory effects, including suppressing macrophage infiltration, in various inflammatory models. We examined whether a DPP‐4 inhibitor, anagliptin, could suppress the growth of IAs in a rodent aneurysm model. METHODS AND RESULTS: IAs were surgically induced in 7‐week‐old male Sprague Dawley rats, followed by oral administration of 300 mg/kg anagliptin. We measured the morphologic parameters of aneurysms over time and their local inflammatory responses. To investigate the molecular mechanisms, we used lipopolysaccharide‐treated RAW264.7 macrophages. In the anagliptin‐treated group, aneurysms were significantly smaller 2 to 4 weeks after IA induction. Anagliptin inhibited the accumulation of macrophages in IAs, reduced the expression of MCP‐1 (monocyte chemotactic protein 1), and suppressed the phosphorylation of p65. In lipopolysaccharide‐stimulated RAW264.7 cells, anagliptin treatment significantly reduced the production of tumor necrosis factor α, MCP‐1, and IL‐6 (interleukin 6) independent of GLP‐1 (glucagon‐like peptide 1), the key mediator in the antidiabetic effects of DPP‐4 inhibitors. Notably, anagliptin activated ERK5 (extracellular signal–regulated kinase 5), which mediates the anti‐inflammatory effects of statins, in RAW264.7 macrophages. Preadministration with an ERK5 inhibitor blocked the inhibitory effect of anagliptin on MCP‐1 and IL‐6 expression. Accordingly, the ERK5 inhibitor also counteracted the suppression of p65 phosphorylation in vitro. CONCLUSIONS: A DPP‐4 inhibitor, anagliptin, prevents the growth of IAs via its anti‐inflammatory effects on macrophages.
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spelling pubmed-56691472017-11-09 Dipeptidyl Peptidase‐4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation Ikedo, Taichi Minami, Manabu Kataoka, Hiroharu Hayashi, Kosuke Nagata, Manabu Fujikawa, Risako Higuchi, Sei Yasui, Mika Aoki, Tomohiro Fukuda, Miyuki Yokode, Masayuki Miyamoto, Susumu J Am Heart Assoc Original Research BACKGROUND: Chronic inflammation plays a key role in the pathogenesis of intracranial aneurysms (IAs). DPP‐4 (dipeptidyl peptidase‐4) inhibitors have anti‐inflammatory effects, including suppressing macrophage infiltration, in various inflammatory models. We examined whether a DPP‐4 inhibitor, anagliptin, could suppress the growth of IAs in a rodent aneurysm model. METHODS AND RESULTS: IAs were surgically induced in 7‐week‐old male Sprague Dawley rats, followed by oral administration of 300 mg/kg anagliptin. We measured the morphologic parameters of aneurysms over time and their local inflammatory responses. To investigate the molecular mechanisms, we used lipopolysaccharide‐treated RAW264.7 macrophages. In the anagliptin‐treated group, aneurysms were significantly smaller 2 to 4 weeks after IA induction. Anagliptin inhibited the accumulation of macrophages in IAs, reduced the expression of MCP‐1 (monocyte chemotactic protein 1), and suppressed the phosphorylation of p65. In lipopolysaccharide‐stimulated RAW264.7 cells, anagliptin treatment significantly reduced the production of tumor necrosis factor α, MCP‐1, and IL‐6 (interleukin 6) independent of GLP‐1 (glucagon‐like peptide 1), the key mediator in the antidiabetic effects of DPP‐4 inhibitors. Notably, anagliptin activated ERK5 (extracellular signal–regulated kinase 5), which mediates the anti‐inflammatory effects of statins, in RAW264.7 macrophages. Preadministration with an ERK5 inhibitor blocked the inhibitory effect of anagliptin on MCP‐1 and IL‐6 expression. Accordingly, the ERK5 inhibitor also counteracted the suppression of p65 phosphorylation in vitro. CONCLUSIONS: A DPP‐4 inhibitor, anagliptin, prevents the growth of IAs via its anti‐inflammatory effects on macrophages. John Wiley and Sons Inc. 2017-06-19 /pmc/articles/PMC5669147/ /pubmed/28630262 http://dx.doi.org/10.1161/JAHA.116.004777 Text en © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial (http://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Research
Ikedo, Taichi
Minami, Manabu
Kataoka, Hiroharu
Hayashi, Kosuke
Nagata, Manabu
Fujikawa, Risako
Higuchi, Sei
Yasui, Mika
Aoki, Tomohiro
Fukuda, Miyuki
Yokode, Masayuki
Miyamoto, Susumu
Dipeptidyl Peptidase‐4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation
title Dipeptidyl Peptidase‐4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation
title_full Dipeptidyl Peptidase‐4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation
title_fullStr Dipeptidyl Peptidase‐4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation
title_full_unstemmed Dipeptidyl Peptidase‐4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation
title_short Dipeptidyl Peptidase‐4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation
title_sort dipeptidyl peptidase‐4 inhibitor anagliptin prevents intracranial aneurysm growth by suppressing macrophage infiltration and activation
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669147/
https://www.ncbi.nlm.nih.gov/pubmed/28630262
http://dx.doi.org/10.1161/JAHA.116.004777
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