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(Circulation. 2002;105:1485.)
© 2002 American Heart Association, Inc.

Vulnerable Atherosclerotic Plaque Morphology in Apolipoprotein E–Deficient Mice Unable to Make Ascorbic Acid

From the Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC.

Correspondence to Dr Nobuyo Maeda, Department of Pathology and Laboratory Medicine, 710 Brinkhous-Bullitt Building, University of North Carolina, Chapel Hill, NC 27599-7125. E-mail nobuyo{at}med.unc.edu

Background— Oxidative stress is thought to play an important role in atherogenesis, suggesting that antioxidants could prevent coronary artery disease. However, the efficacy of vitamin C in reducing atherosclerosis is debatable in humans and has not been tested rigorously in animals.

Methods and Results— Gulo^-/-Apoe^-/- mice were used to test a hypothesis that chronic vitamin C deficiency enhances the initiation and development of atherosclerosis. These mice are dependent on dietary vitamin C because of the lack of L-gulonolactone--oxidase and are prone to develop atherosclerosis because of lacking apolipoprotein E. Beginning at 6 weeks of age, the Gulo^-/-Apoe^-/- mice were fed regular chow or Western-type diets containing high fat and supplemented with either 0.033 g or 3.3 g/L of vitamin C in their drinking water. This regimen produced mice with chronically low vitamin C (average 1.5 µg/mL in plasma) or high vitamin C (average 10 to 30 µg/mL in plasma). Morphometric analysis showed that within each sex, age, and diet group, the sizes of the atherosclerotic plaques were not different between low vitamin C mice and high vitamin C mice. However, advanced plaques in the low vitamin C mice had significantly reduced amounts of Sirius red–staining collagen (36.4±2.2% versus 54.8±2.3%, P<0.0001), larger necrotic cores within the plaques, and reduced fibroproliferation and neovascularization in the aortic adventitia.

Conclusions— Chronic vitamin C deficiency does not influence the initiation or progression of atherosclerotic plaques but severely compromises collagen deposition and induces a type of plaque morphology that is potentially vulnerable to rupture.

Key Words: antioxidants • atherosclerosis • collagen • plaque rupture • vitamin C

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