AT1 blockade attenuates atherosclerotic plaque destabilization accompanied by the suppression of cathepsin S activity in apoE-deficient mice.
Although it has been suggested that the renin-angiotensin (RA) system and cathepsins contribute to the development and vulnerability of atherosclerotic plaque, the interaction of the RA system and cathepsins is unclear. Thus, we investigated the effects of an angiotensin II type 1 receptor (AT1) antagonist, olmesartan, on the levels of cathepsins in brachiocephalic atherosclerotic plaque and plaque stabilization in apolipoprotein E (apoE)-deficient mice receiving a high-fat diet. Under a high fat diet, treatment with olmesartan (3 mg/kg per day) maintained collagen and elastin at high levels and attenuated the plaque development and cathepsin S (Cat S) level in the atherosclerotic plaque of apoE-deficient mice. The administration of olmesartan suppressed the accumulation of macrophages in plaque. Immunoreactivities of Cat S and AT1 were observed in macrophages. The amount of Cat S mRNA and the macrophage-mediated collagenolytic and elastolytic activities in cultured macrophages were increased by exposure to angiotensin II (Ang II), and these effects were diminished by olmesartan and the NADPH-oxidase inhibitor apocynin. These results suggested that Cat S derived from macrophages is involved in the mechanisms of atherosclerotic plaque vulnerability, and AT1 blocker maintained the plaque stabilization alongside the suppression of Cat S and macrophage activities.
Sasaki
Takeshi
T
Department of Anatomy and Neuroscience, Hamamatsu University School of Medicine, 1 Handayama, Higashi-ku, Hamamatsu, Shizuoka, Japan.
Kuzuya
Masafumi
M
Nakamura
Kae
K
Cheng
Xian Wu
XW
Hayashi
Taiju
T
Song
Haizhen
H
Hu
Lina
L
Okumura
Kenji
K
Murohara
Toyoaki
T
Iguchi
Akihisa
A
Sato
Kohji
K
D000803:Angiotensin I / Q000378:metabolism*; D000821:Animal Feed; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000378:metabolism*; D002403:Cathepsins / Q000378:metabolism*; D003094:Collagen / Q000737:chemistry; D004041:Dietary Fats; D004549:Elastin / Q000737:chemistry; D007093:Imidazoles / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology; D008297:Male; D051379:Mice; D018384:Oxidative Stress; D012084:Renin-Angiotensin System; D013777:Tetrazoles / Q000494:pharmacology
D001057:Apolipoproteins E; D004041:Dietary Fats; D007093:Imidazoles; D013777:Tetrazoles; C437965:olmesartan; D003094:Collagen; D004549:Elastin; D000803:Angiotensin I; D002403:Cathepsins; C028217:cathepsin S