© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Oxidative stress in the pathogenesis of thoracic aortic aneurysm
Protective role of statin and angiotensin II type 1 receptor blocker
aDivision of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, chuo-ku, Kobe 650-0017, Japan
bDivision of Cardiovascular, Thoracic, and Pediatric Surgery, Department of Vascular Medicine, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, chuo-ku, Kobe 650-0017, Japan
cDivision of Surgical Pathology, Department of Biological Informatics, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, chuo-ku, Kobe 650-0017, Japan
dDivision of Molecular Biology, Department of Basic Medical Sciences, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
nobutaka{at}med.kobe-u.ac.jp
* Corresponding author. Tel.: +81-78-382-5846; fax: +81-78-382-5859.
Objective: The pathogenesis of thoracic aortic aneurysms (TAA) is still unclear. A recent investigation indicated that angiotensin II, a potent activator of NADH/NADPH oxidase, plays an important role in aneurysmal formation. We investigated the potential role of p22phox-based NADH/NADPH oxidase in the pathogenesis of TAA. Methods: Human thoracic aneurysmal (n=40) and non-aneurysmal (control, n=39) aortic sections were examined, and the localization of p22phox, an essential component of the oxidase, and its expressional differences were investigated by immunohistochemistry and Western blot. In situ reactive oxygen species (ROS) generation was examined by the dihydroethidium method, and the impact of medical treatment on p22phox expression was investigated by multiple regression analysis. Results: In situ production of ROS and the expression of p22phox increased markedly in TAA throughout the wall, and Western blot confirmed the enhanced expression of p22phox. The expression was more intense in the regions where monocytes/macrophages accumulated. In these inflammatory regions, numerous chymase-positive mast cells and angiotensin converting enzyme-positive macrophages were present. Their localization closely overlapped the in situ activity of matrix metalloproteinase and the expression of p22phox. Multiple regression analysis revealed that medical treatment with statin and angiotensin II type 1 receptor blocker (ARB) suppressed p22phox expression in TAA. Conclusion: Our findings indicate the role of p22phox-based NADH/NADPH oxidase and the local renin–angiotensin system in the pathogenesis of TAA. Statin and ARB might have inhibitory effects on the formation of aneurysms via hrough the suppression of NADH/NADPH oxidase.
KEYWORDS ACE, angiotensin converting enzyme; Ang II, angiotensin II; ARB, angiotensin II type 1 receptor blocker; CABG, coronary artery bypass graft surgery; CRP, C-reactive protein; MMP, matrix metalloproteinase; ROS, reactive oxygen species; SMC, smooth muscle cell; TAA, thoracic aortic aneurysms
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