Published Online
on March 4, 2002

A more recent version of this article appeared on March 26, 2002

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Submitted on November 19, 2001
Revised on January 18, 2002
Accepted on January 18, 2002

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

Yukiko Nakata MD, PhD and Nobuyo Maeda PhD^*

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

^* To whom correspondence should be addressed. 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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