Oxidative stress in the pathogenesis of thoracic aortic aneurysm: protective role of statin and angiotensin II type 1 receptor blocker.
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.


CONCLUSIONS
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 the suppression of NADH/NADPH oxidase.
Ejiri
Junya
J
Division 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.
Inoue
Nobutaka
N
Tsukube
Takuro
T
Munezane
Takashi
T
Hino
Yutaka
Y
Kobayashi
Seiichi
S
Hirata
Ken-ichi
K
Kawashima
Seinosuke
S
Imajoh-Ohmi
Shinobu
S
Hayashi
Yoshitake
Y
Yokozaki
Hiroshi
H
Okita
Yutaka
Y
Yokoyama
Mitsuhiro
M
D000368:Aged; D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001013:Aorta, Thoracic / Q000378:metabolism*; D017545:Aortic Aneurysm, Thoracic / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D015153:Blotting, Western / Q000379:methods; D016022:Case-Control Studies; D053818:Chymases; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D007150:Immunohistochemistry / Q000379:methods; D007249:Inflammation; D008264:Macrophages / Q000201:enzymology; D008297:Male; D008407:Mast Cells / Q000201:enzymology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000032:analysis; D009252:NADPH Dehydrogenase / Q000032:analysis; D019255:NADPH Oxidases; D018384:Oxidative Stress; D007703:Peptidyl-Dipeptidase A / Q000032:analysis; D010750:Phosphoproteins / Q000032:analysis; D012044:Regression Analysis; D012697:Serine Endopeptidases / Q000032:analysis
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D026901:Membrane Transport Proteins; D010750:Phosphoproteins; D019255:NADPH Oxidases; C086986:CYBA protein, human; D009252:NADPH Dehydrogenase; D007703:Peptidyl-Dipeptidase A; D012697:Serine Endopeptidases; D053818:Chymases; D020782:Matrix Metalloproteinases