Vulnerable atherosclerotic plaque morphology in apolipoprotein E-deficient mice unable to make ascorbic Acid

Circulation. 2002 Mar 26;105(12):1485-90. doi: 10.1161/01.cir.0000012142.69612.25.

Abstract

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-gamma-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 microg/mL in plasma) or high vitamin C (average 10 to 30 microg/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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Aorta / metabolism
  • Aorta / pathology
  • Apolipoproteins E / deficiency*
  • Apolipoproteins E / genetics
  • Arteriosclerosis / complications
  • Arteriosclerosis / metabolism
  • Arteriosclerosis / pathology*
  • Ascorbic Acid / genetics*
  • Ascorbic Acid / metabolism
  • Ascorbic Acid Deficiency / complications
  • Ascorbic Acid Deficiency / metabolism
  • Ascorbic Acid Deficiency / pathology*
  • Blood Glucose
  • Cholesterol / blood
  • Cholesterol, HDL / blood
  • Collagen / metabolism
  • Crosses, Genetic
  • Dietary Fats
  • Dietary Supplements
  • Disease Models, Animal
  • Disease Progression
  • Female
  • L-Gulonolactone Oxidase
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Sex Factors
  • Sugar Alcohol Dehydrogenases / deficiency
  • Sugar Alcohol Dehydrogenases / genetics
  • Triglycerides / blood

Substances

  • Apolipoproteins E
  • Blood Glucose
  • Cholesterol, HDL
  • Dietary Fats
  • Triglycerides
  • Collagen
  • Cholesterol
  • Sugar Alcohol Dehydrogenases
  • L-Gulonolactone Oxidase
  • Ascorbic Acid