title: Blockade of renin-angiotensin system attenuates advanced glycation end products-mediated signaling pathways.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  We used cultured rabbit aortic smooth muscle cells (SMCs), which were stimulated with AGE in the presence or absence of temocaprilat or olmesartan.
  
  
  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-kappaB 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cardiology and Hematology, Fukushima Medical University, Fukushima, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Kamioka
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Ishibashi
authors.forename: Koichi
authors.initials: K
authors.lastname: Sugimoto
authors.forename: Hironori
authors.initials: H
authors.lastname: Uekita
authors.forename: Ryoji
authors.initials: R
authors.lastname: Nagai
authors.forename: Nobuo
authors.initials: N
authors.lastname: Sakamoto
authors.forename: Katsuya
authors.initials: K
authors.lastname: Ando
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohkawara
authors.forename: Tamio
authors.initials: T
authors.lastname: Teramoto
authors.forename: Yukio
authors.initials: Y
authors.lastname: Maruyama
authors.forename: Yasuchika
authors.initials: Y
authors.lastname: Takeishi
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000166:cytology; D002478:Cells, Cultured; D003925:Diabetic Angiopathies / Q000188:drug therapy; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D032389:Myocytes, Smooth Muscle; D019255:NADPH Oxidases / Q000378:metabolism; D011817:Rabbits; D012084:Renin-Angiotensin System / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D013777:Tetrazoles / Q000494:pharmacology; D013841:Thiazepines / Q000494:pharmacology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D017127:Glycation End Products, Advanced; D007093:Imidazoles; D013777:Tetrazoles; D013841:Thiazepines; C069156:temocaprilat; C437965:olmesartan; D019255:NADPH Oxidases