Blockade of renin-angiotensin system attenuates advanced glycation end products-mediated signaling pathways.
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.
Kamioka
Masashi
M
Department of Cardiology and Hematology, Fukushima Medical University, Fukushima, Japan.
Ishibashi
Toshiyuki
T
Sugimoto
Koichi
K
Uekita
Hironori
H
Nagai
Ryoji
R
Sakamoto
Nobuo
N
Ando
Katsuya
K
Ohkawara
Hiroshi
H
Teramoto
Tamio
T
Maruyama
Yukio
Y
Takeishi
Yasuchika
Y
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
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