Aortic wall damage in mice unable to synthesize ascorbic acid

Nobuyo Maeda, Hiroyuki Hagihara, Yukiko Nakata, Sylvia Hiller, Jennifer Wilder, Robert Reddick

Research output: Contribution to journalArticlepeer-review

193 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)841-846
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number2
DOIs
StatePublished - Jan 18 2000

ASJC Scopus subject areas

  • General

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