Aortic wall damage in mice unable to synthesize ascorbic acid.
By inactivating the gene for L-gulono-gamma-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.
Maeda
N
N
Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599-7525, USA. nobuyo@med.unc.edu
Hagihara
H
H
Nakata
Y
Y
Hiller
S
S
Wilder
J
J
Reddick
R
R
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001013:Aorta, Thoracic / Q000201:enzymology / Q000473:pathology* / Q000648:ultrastructure; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000096:biosynthesis* / Q000097:blood; D001206:Ascorbic Acid Deficiency / Q000201:enzymology / Q000235:genetics; D002455:Cell Division; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D004032:Diet; D004547:Elastic Tissue / Q000473:pathology / Q000648:ultrastructure; D005260:Female; D005838:Genotype; D006720:Homozygote; D050544:L-Gulonolactone Oxidase; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008854:Microscopy, Electron; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D016297:Mutagenesis, Site-Directed; D051381:Rats; D013401:Sugar Alcohol Dehydrogenases / Q000235:genetics / Q000378:metabolism
D000975:Antioxidants; D008076:Cholesterol, HDL; D002784:Cholesterol; D013401:Sugar Alcohol Dehydrogenases; D050544:L-Gulonolactone Oxidase; D001205:Ascorbic Acid