title: Combined vitamin C and vitamin E deficiency worsens early atherosclerosis in apolipoprotein E-deficient mice.
abstract: OBJECTIVE
  To assess the role of combined deficiencies of vitamins C and E on the earliest stages of atherosclerosis (an inflammatory condition associated with oxidative stress), 4 combinations of vitamin supplementation (low C/low E, low C/high E, high C/low E, and high C/high E) were studied in atherosclerosis-prone apolipoprotein E-deficient mice also unable to synthesize their own vitamin C (gulonolactone oxidase(-/-)); and to evaluate the effect of a more severe depletion of vitamin C alone in a second experiment using gulonolactone oxidase(-/-) mice carrying the hemizygous deletion of SVCT2 (the vitamin C transporter).
  
  
  RESULTS
  After 8 weeks of a high-fat diet (16% lard and 0.2% cholesterol), atherosclerosis developed in the aortic sinus areas of mice in all diet groups. Each vitamin-deficient diet significantly decreased liver and brain contents of the corresponding vitamin. Combined deficiency of both vitamins increased lipid peroxidation, doubled plaque size, and increased plaque macrophage content by 2- to 3-fold in male mice, although only plaque macrophage content was increased in female mice. A more severe deficiency of vitamin C in gulonolactone oxidase(-/-) mice with defective cellular uptake of vitamin C increased both oxidative stress and atherosclerosis in apolipoprotein E(-/-) mice compared with littermates receiving a diet replete in vitamin C, again most clearly in males.
  
  
  CONCLUSIONS
  Combined deficiencies of vitamins E and C are required to worsen early atherosclerosis in an apolipoprotein E-deficient mouse model. However, a more severe cellular deficiency of vitamin C alone promotes atherosclerosis when vitamin E is replete.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-0475, USA.
authors.forename: Vladimir R
authors.initials: VR
authors.lastname: Babaev
authors.forename: Liying
authors.initials: L
authors.lastname: Li
authors.forename: Sanket
authors.initials: S
authors.lastname: Shah
authors.forename: Sergio
authors.initials: S
authors.lastname: Fazio
authors.forename: MacRae F
authors.initials: MF
authors.lastname: Linton
authors.forename: James M
authors.initials: JM
authors.lastname: May
mesh_terms: D000818:Animals; D001018:Aortic Diseases / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001205:Ascorbic Acid / Q000378:metabolism / Q000494:pharmacology; D001206:Ascorbic Acid Deficiency / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D050197:Atherosclerosis / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism; D019587:Dietary Supplements; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D050544:L-Gulonolactone Oxidase / Q000172:deficiency / Q000235:genetics; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D029363:Organic Anion Transporters, Sodium-Dependent / Q000172:deficiency / Q000235:genetics; D018384:Oxidative Stress; D012720:Severity of Illness Index; D012737:Sex Factors; D060347:Sodium-Coupled Vitamin C Transporters; D027981:Symporters / Q000172:deficiency / Q000235:genetics; D013997:Time Factors; D014810:Vitamin E / Q000378:metabolism / Q000494:pharmacology; D014811:Vitamin E Deficiency / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D014815:Vitamins / Q000378:metabolism / Q000494:pharmacology
chemical_list: D001057:Apolipoproteins E; D029363:Organic Anion Transporters, Sodium-Dependent; C555165:Slc23a2 protein, mouse; D060347:Sodium-Coupled Vitamin C Transporters; D027981:Symporters; D014815:Vitamins; D014810:Vitamin E; D050544:L-Gulonolactone Oxidase; D001205:Ascorbic Acid