title: A cardiovascular phenotype in warfarin-resistant Vkorc1 mutant rats.
abstract: 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.
authors.affiliation: Department of Ecology & Evolutionary Biology, Institute of Biosciences and Bioengineering, Rice University, MS 170, 6100 Main Street, Houston, Texas 77005, U.S.A.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Kohn
authors.forename: Roger E
authors.initials: RE
authors.lastname: Price
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Pelz