Aortic Wall Damage in Mice Unable to Synthesize Ascorbic Acid

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 97; no. 2; pp. 841 - 846
• Main Authors: Maeda, Nobuyo, Hagihara, Hiroyuki, Nakata, Yukiko, Hiller, Sylvia, Wilder, Jennifer, Reddick, Robert
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 18-01-2000; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Animals; Antioxidants - metabolism; Aorta, Thoracic - enzymology; Aorta, Thoracic - pathology; Aorta, Thoracic - ultrastructure; ascorbic acid; Ascorbic Acid - administration & dosage; Ascorbic Acid - biosynthesis; Ascorbic Acid - blood; Ascorbic Acid Deficiency - enzymology; Ascorbic Acid Deficiency - genetics; Biological Sciences; Cell Division; Cholesterol - blood; Cholesterol, HDL - blood; Cholesterols; Diet; Elastic Tissue - pathology; Elastic Tissue - ultrastructure; Enzymes; Exons; Female; Genes; Genotype; Genotypes; HDL lipoproteins; Heart; Homozygote; Homozygotes; L-Gulonolactone Oxidase; Lipoproteins; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Microscopy, Electron; Muscle, Smooth, Vascular - cytology; Mutagenesis, Site-Directed; Rats; Rodents; Sugar Alcohol Dehydrogenases - genetics; Sugar Alcohol Dehydrogenases - metabolism; Thoracic aorta; Vitamin C
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.97.2.841

By inactivating the gene for L-gulono-γ -lactone oxidase, a key enzyme in ascorbic acid synthesis, we have generated mice that, like humans, depend on dietary vitamin C. Regular chow, containing about 110 mg/kg of vitamin C, is unable to support the growth of the mutant mice, which require L-ascorbic acid supplemented in their drinking water (330 mg/liter). Upon withdrawal of supplementation, plasma and tissue ascorbic acid levels decreased to 10-15% of normal within 2 weeks, and after 5 weeks the mutants became anemic, began to lose weight, and die. Plasma total antioxidative capacities were approximately 37% normal in homozygotes after feeding the unsupplemented diet for 3-5 weeks. As plasma ascorbic acid decreased, small, but significant, increases in total cholesterol and decreases in high density lipoprotein cholesterol were observed. The most striking effects of the marginal dietary vitamin C were alterations in the wall of aorta, evidenced by the disruption of elastic laminae, smooth muscle cell proliferation, and focal endothelial desquamation of the luminal surface. Thus, marginal vitamin C deficiency affects the vascular integrity of mice unable to synthesize ascorbic acid, with potentially profound effects on the pathogenesis of vascular diseases. Breeding the vitamin C-dependent mice with mice carrying defined genetic mutations will provide numerous opportunities for systematic studies of the role of antioxidants in health and disease.