Aortic wall damage in mice unable to synthesize ascorbic acid

By inactivating the gene for L-gulono-gamma-lactone oxidase, a key enzyme i n 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-asco rbic acid supplemented in their drinking water (330 mg/liter). Upon withdra wal of supplementation, plasma and tissue ascorbic acid levels decreased to 10-15% of normal within 2 weeks, and after 5 weeks the mutants became anem ic, began to lose weight, and die. Plasma total antioxidative capacities we re approximately 37% normal in homozygotes after feeding the unsupplemented diet for 3-5 weeks. As plasma ascorbic acid decreased, small, but signific ant, increases in total cholesterol and decreases in high density lipoprote in cholesterol were observed. The most striking effects of the marginal die tary vitamin C were alterations in the wall of aorta, evidenced by the disr uption of elastic laminae, smooth muscle cell proliferation, and focal endo thelial desquamation of the luminal surface. Thus, marginal vitamin C defic iency affects the vascular integrity of mice unable to synthesize ascorbic acid, with potentially profound effects on the pathogenesis of vascular dis eases. Breeding the vitamin C-dependent mice with mice carrying defined gen etic mutations will provide numerous opportunities for systematic studies o f the role of antioxidants in health and disease.