Failure of antioxidants to protect against angiotensin II‐induced aortic rupture in aged apolipoprotein(E)‐deficient mice

• Published in: British journal of pharmacology 2007-11, Vol.152 (6), p.880-890
• Main Authors: Jiang, F, Jones, G T, Dusting, G J
• Format: Article
• Language: English
• Subjects: abdominal aortic aneurysm; aged; Aging - physiology; angiotensin II; Angiotensin II - antagonists & inhibitors; Angiotensin II - toxicity; Animals; antioxidants; Antioxidants - pharmacology; aortic rupture; Aortic Rupture - chemically induced; Aortic Rupture - prevention & control; apolipoprotein E‐deficient; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Biological and medical sciences; Blood Pressure - drug effects; Blood Pressure - physiology; Blotting, Western; Creatinine - blood; Heme Oxygenase-1 - metabolism; Humans; Immunohistochemistry; Kidney - drug effects; Kidney Function Tests; Male; Matrix Metalloproteinase 9 - metabolism; Medical sciences; metalloproteinase; Mice; Mice, Knockout; Oxidative Stress - drug effects; Pharmacology. Drug treatments; Proteinuria - chemically induced; Proteinuria - prevention & control; Research Papers; Thiobarbituric Acid Reactive Substances - metabolism; U937 Cells
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0707449

Background and purpose: Oxidative stress may be involved in the development of abdominal aortic aneurysms (AAAs). Previous studies indicate that antioxidants protect against AAA formation during chronic angiotensin (Ang) II infusion in apolipoprotein E‐deficient (ApoE0) mice. We here examine if these protective effects also occurred in aged ApoE0 mice. Experimental approach: Male ApoE0 mice (50–60 weeks) were randomly divided into 4 groups: saline, Ang II (1000 ng kg−1 min−1 for 4 weeks), Ang II plus antioxidants (0.1% vitamin E in food plus 0.1% vitamin C in drinking water), and Ang II plus losartan (30 mg kg−1 day−1). Key results: Exogenous Ang II increased systolic blood pressure by 40 mmHg and resulted in the formation of pseudoaneurysms (rupture and extramural haematoma) in the abdominal aorta in 50% of animals. True aneurysmal dilatation was rarely observed. Antioxidants decreased systemic oxidative stress (plasma malondialdehyde), but had only minor effects on aortic rupture, relative to the complete prevention by losartan. Immunohistochemistry revealed strong matrix metalloproteinase‐9 (MMP‐9) expression in atherosclerotic plaques and at the sites of rupture. Antioxidants did not affect tumour necrosis factor‐α‐stimulated MMP‐9 release from U937 cells. In addition, antioxidants had little effects on Ang II‐induced renal dysfunction. Conclusions and implications: In contrast to previous findings in younger mice, antioxidants had only minor effects on Ang II‐induced aortic rupture in aged mice. Our results demonstrate that the pathological features of the aneurysmal remodelling induced by Ang II in old ApoE0 mice are distinct from those of human AAA. British Journal of Pharmacology (2007) 152, 880–890; doi:10.1038/sj.bjp.0707449; published online 10 September 2007