Aortic wall damage in mice unable to synthesize ascorbic acid

摘要

By inactivating the gene for L-gulono-y-lactone oxidase, a key enzyme in ascorbic acid synthesis, we have generated mice that, like humans, depend on dietary vitamin C. Regular chow, contain- ing 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 supple- mentation, plasma and tissue ascorbic acid levels decreased to 10--1 S/100 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 37/100 normal in ho- mozygotes 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 mar- ginal 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 poten- tially 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 sys- tematic studies of the role of antioxidants in health and disease.