Background— Angiotensin II (Ang II) contributes to vascular pathology in part by stimulating NADPH oxidase activity, leading to increased formation of superoxide (O 2 − ). We reported that O 2 − levels, NADPH oxidase activity, and expression of the p47 phox subunit of NADPH oxidase are increased in human abdominal aortic aneurysms (AAAs). Here, we tested the hypothesis that deletion of p47 phox will attenuate oxidative stress and AAA formation in Ang II–infused apoE −/− mice. Methods and Results— Male apoE −/− and apoE −/− p47 phox −/− mice received saline or Ang II (1000 ng · kg −1 · min −1 ) infusion for 28 days, after which abdominal aortic weight and maximal diameter were determined. Aortic tissues and blood were examined for parameters of aneurysmal disease and oxidative stress. Ang II infusion induced AAAs in 90% of apoE −/− versus 16% of apo −/− p47 phox −/− mice ( P <0.05). Abdominal aortic weight (14.1±3.2 versus 35.6±9.0 mg), maximal aortic diameter (1.5±0.2 versus 2.4±0.4 mm), aortic NADPH oxidase activity, and parameters of oxidative stress were reduced in apoE −/− p47 phox −/− mice compared with apoE −/− mice ( P <0.05). In addition, aortic macrophage infiltration and matrix metalloproteinase-2 activity were reduced in apoE −/− p47 phox −/− mice compared with apoE −/− mice. Deletion of p47 phox attenuated the pressor response to Ang II; however, coinfusion of phenylephrine with Ang II, which restored the Ang II pressor response, did not alter the protective effects of p47 phox deletion on AAA formation. Conclusions— Deletion of p47 phox attenuates Ang II–induced AAA formation in apoE −/− mice, suggesting that NADPH oxidase plays a critical role in AAA formation in this model.
Background-Abdominal aortic aneurysms (AAAs) in humans are associated with locally increased oxidative stress and activity of NADPH oxidase. We investigated the hypothesis that vitamin E, an antioxidant with documented efficacy in mice, can attenuate AAA formation during angiotensin II (Ang II) infusion in apolipoprotein E-deficient mice. Methods and Results-Six-month-old male apolipoprotein E-deficient mice were infused with Ang II at 1000 ng/kg per minute for 4 weeks via osmotic minipumps while consuming either a regular diet or a diet enriched with vitamin E (2 IU/g of diet). After 4 weeks, abdominal aortic weight and maximal diameter were determined, and aortic tissues were sectioned and examined using biochemical and histological techniques. Vitamin E attenuated formation of AAA, decreasing maximal aortic diameter by 24% and abdominal aortic weight by 34% (PϽ0.05, respectively). Importantly, animals treated with vitamin E showed a 44% reduction in the combined end point of fatalϩnonfatal aortic rupture (PϽ0.05). Vitamin E also decreased aortic 8-isoprostane content (a marker of oxidative stress) and reduced both aortic macrophage infiltration and osteopontin expression (PϽ0.05, respectively). Vitamin E treatment had no significant effect on the extent of aortic root atherosclerosis, activation of matrix metalloproteinases 2 or 9, serum lipid profile, or systolic blood pressure. Key Words: aneurysm Ⅲ vitamin E Ⅲ oxidative stress Ⅲ vascular inflammation Ⅲ NADPH oxidase Ⅲ osteopontin A bdominal aortic aneurysms (AAAs) occur in Ϸ3% of humans Ͼ65 years of age and are characterized by localized structural deterioration of the aortic wall, leading to progressive aortic dilation. The most dreaded complication of AAA is rupture, the likelihood of which is directly related to aneurysm diameter. 1 Although open surgical repair can improve outcomes in patients with large AAAs, the procedure is associated with significant operative risks and complications, particularly in the presence of comorbid conditions common in these patients. Percutaneous repair techniques (ie, stent grafting) have been developed, but not all patients are candidates, and these procedures are also associated with significant complications. 2 The development of effective medical therapy for AAA has been hampered by lack of understanding of the mechanisms responsible for aneurysm growth and rupture. Conclusions-VitaminStudies published over the past decade support the view that inflammation plays a key role in the pathogenesis of AAAs. [3][4][5][6][7] One of the known causes and consequences of inflammation is an increase in local levels of oxidative stress.Indeed, Miller et al have shown that human aneurysmal aorta displays clear evidence of increased oxidative damage and pro-oxidant enzyme expression/activity compared with adjacent nonaneurysmal tissue. 8 Whether oxidative stress is merely associated with AAAs, or whether it contributes to the pathogenesis of the disease, remains to be determined.In the present study, we examined the effects of ...
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