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

• Kamioka Masashi

  Department of Cardiology and Hematology, Fukushima Medical University.

• Ishibashi Toshiyuki

  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.

• Ohkawara Hiroshi

  Department of Cardiology and Hematology, Fukushima Medical University.

• Teramoto Tamio

  Department of Internal Medicine, Teikyo University School of Medicine.

• Maruyama Yukio

  Hoshi General Hospital.

• Takeishi Yasuchika

  Department of Cardiology and Hematology, Fukushima Medical University.

抄録

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^phox 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.

収録刊行物

• Ｊｏｕｒｎａｌ　ｏｆ　Ａｔｈｅｒｏｓｃｌｅｒｏｓｉｓ　ａｎｄ　Ｔｈｒｏｍｂｏｓｉｓ

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

  一般社団法人 日本動脈硬化学会

キーワード

• Rac1
• MMP-9
• Apoptosis
• ACE inhibitor
• ARB

詳細情報

• CRID: 1390001204432457344
• NII論文ID: 130004845319
• DOI: 10.5551/jat.3624
• ISSN: 18803873
• ISSN: 13403478
• Web Site: https://search.jamas.or.jp/link/ui/2011079945
• 本文言語コード: en
• データソース種別:
  • JaLC
  • Crossref
  • CiNii Articles
• 抄録ライセンスフラグ: 使用不可