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A cardiovascular phenotype in warfarin-resistant Vkorc1 mutant rats.

Authors: Kohn, MH  Price, RE  Pelz, HJ 
Citation: Kohn MH, etal., Artery Res. 2008 Nov;2(4):138-147.
Pubmed: (View Article at PubMed) PMID:19884975
DOI: Full-text: DOI:10.1016/j.artres.2008.09.002

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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CRRD Object Information
CRRD ID: 2315841
Created: 2010-01-13
Species: All species
Last Modified: 2010-01-13
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.