| 19884975 |
Kohn MH, Price RE, Pelz HJ: A cardiovascular phenotype in warfarin-resistant Vkorc1 mutant rats. Artery Res. 2008 Nov;2(4):138-147.
BACKGROUND: The inhibition of the vitamin K cycle by warfarin promotes arterial calcification in the rat. Conceivably, genetically determined vitamin K-deficiency owing to a mutant epoxide reductase subcomponent 1 (Vkorc1) gene, a key component of the vitamin K cycle, might also promote arterial calcification. In the absence of an available Vkorc1 gene knockout model we used a wild-derived Vkorc1 mutant rat strain (Rattus norvegicus) to explore the validity of this hypothesis. METHODS: We provide histopathological descriptions of a naturally occurring Vkorc1 gene knockdown: wild-derived lab-reared rats that are resistant to the anticoagulant warfarin owing to a non-synonymous mutation in the Vkorc1 gene (Vkorc1 (Y-> C)), which, in vitro, reduces the basal activity of the vitamin K epoxide reductase enzyme complex by ~52%. H&E; stained sections of heart and kidney were compared between homozygous Vkorc1 (Y-> C/ Y-> C), heterozygous Vkorc1 (Y-> C/+) and wildtype Vkorc1 (+/+) rats of both sexes. RESULTS: We observed that the aorta of the heart was mineralized in the Vkorc1 (Y-> C/ Y-> C) male rats but lesions were virtually absent from Vkorc1 (Y-> C/+) and Vkorc1 (+/+) male and all female rats. The renal arteries were mineralized in Vkorc1 (Y-> C/ Y-> C) and Vkorc1 (Y-> C/+) mutant rats, regardless of sex. CONCLUSIONS: Results support a hypothesis that posits that Vkorc1 genetic polymorphisms reducing basal enzyme activity could affect cardiovascular health, with dependencies on genotype, sex, and tissue. The undercarboxylation of the vitamin K-dependent Matrix Gla protein may be the crucial component of the pathway promoting this mineralization. |
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