Combined Vitamin C and Vitamin E Deficiency Worsens Early Atherosclerosis in Apolipoprotein E–Deficient Mice

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 30; no. 9; pp. 1751 - 1757
• Main Authors: Babaev, Vladimir R, Li, Liying, Shah, Sanket, Fazio, Sergio, Linton, MacRae F, May, James M
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.09.2010; Lippincott Williams & Wilkins
• Subjects: Animals; Aortic Diseases - drug therapy; Aortic Diseases - etiology; Aortic Diseases - genetics; Aortic Diseases - metabolism; Aortic Diseases - pathology; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Ascorbic Acid - metabolism; Ascorbic Acid - pharmacology; Ascorbic Acid Deficiency - complications; Ascorbic Acid Deficiency - drug therapy; Ascorbic Acid Deficiency - metabolism; Atherosclerosis (general aspects, experimental research); Atherosclerosis - drug therapy; Atherosclerosis - etiology; Atherosclerosis - genetics; Atherosclerosis - metabolism; Atherosclerosis - pathology; Biological and medical sciences; Blood and lymphatic vessels; Brain - metabolism; Cardiology. Vascular system; Dietary Supplements; Disease Models, Animal; Disease Progression; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Female; L-Gulonolactone Oxidase - deficiency; L-Gulonolactone Oxidase - genetics; Lipid Peroxidation; Liver - metabolism; Macrophages - metabolism; Macrophages - pathology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardium - metabolism; Organic Anion Transporters, Sodium-Dependent - deficiency; Organic Anion Transporters, Sodium-Dependent - genetics; Orthopedic surgery; Oxidative Stress; Severity of Illness Index; Sex Factors; Sodium-Coupled Vitamin C Transporters; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Symporters - deficiency; Symporters - genetics; Time Factors; Vitamin E - metabolism; Vitamin E - pharmacology; Vitamin E Deficiency - complications; Vitamin E Deficiency - drug therapy; Vitamin E Deficiency - metabolism; Vitamins - metabolism; Vitamins - pharmacology; antioxidants; Rodentia; Nutrition disorder; Cardiovascular disease; Antioxidant; genetically altered mice; Vascular disease; Vertebrata; nutrition; Mammalia; Mouse; Apolipoprotein E; Animal; Atherosclerosis
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.110.209502

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). METHODS AND 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. CONCLUSION—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.