Blockade of Renin-Angiotensin System Attenuates Advanced Glycation End Products-Mediated Signaling Pathways

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Author(s)

    • Kamioka Masashi
    • Department of Cardiology and Hematology, Fukushima Medical University.
    • Sugimoto Koichi
    • Department of Cardiology and Hematology, Fukushima Medical University.
    • Uekita Hironori
    • Department of Cardiology and Hematology, Fukushima Medical University.
    • Nagai Ryoji
    • Department of Food and Nutrition, Laboratory of Biochemistry & Nutritional Science, Japan Women's University.
    • Sakamoto Nobuo
    • Department of Cardiology and Hematology, Fukushima Medical University.
    • Ando Katsuya
    • Department of Cardiology and Hematology, Fukushima Medical University.
    • Teramoto Tamio
    • Department of Internal Medicine, Teikyo University School of Medicine.

Abstract

Aim: Advanced glycation end products (AGE) and a receptor for AGE (RAGE) play a key role in diabetic vascular complications. Matrix metalloproteinases (MMPs) and apoptosis contribute to plaque instability. The renin-angiotensin system (RAS) is crucial for NADPH oxidase-dependent redox signaling pathways in the vascular wall. We investigated the effects of RAS blockade on AGE-triggered signaling pathways and its downstream events, including MMP-9 and apoptosis.<BR>Methods: We used cultured rabbit aortic smooth muscle cells (SMCs), which were stimulated with AGE in the presence or absence of temocaprilat or olmesartan.<BR>Results: Angiotensin converting enzyme (ACE) mRNA levels were increased 4 to 6 hours after adding AGE. AGE induced Rac1 and p47<sup>phox</sup> membrane translocation, reactive oxygen species (ROS) generation and NF-κB phosphorylation within 15 minutes, and various molecular expressions after 18 hours, which were attenuated by RAS blockade by temocaprilat or olmesartan. AGE-induced RAGE expression, as well as other molecules, including membrane type 1-MMP (MT1-MMP), monocyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1), was NADPH oxidase signaling-dependent and blunted by temocaprilat and olmesartan. The parameters of plaque instability, including MMP-9 expression and activity, and apoptosis were up-regulated by AGE, which was markedly attenuated by temocaprilat or olmesartan. Using isolated human monocyte culture, AGE-induced ROS generation and molecular expression were also attenuated by RAS blockade.<BR>Conclusion: The present study shows that AGE-triggered NADPH oxidase signaling pathways, including MMP-9 and apoptosis, were attenuated by RAS blockade, which may be an attractive strategy for treating plaque instability in diabetic vascular complications.

Journal

  • Journal of Atherosclerosis and Thrombosis

    Journal of Atherosclerosis and Thrombosis 17(6), 590-600, 2010

    Japan Atherosclerosis Society

Codes

  • NII Article ID (NAID)
    130004845319
  • Text Lang
    ENG
  • ISSN
    1340-3478
  • Data Source
    J-STAGE 
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