A cardiovascular phenotype in warfarin-resistant Vkorc1 mutant rats☆
Received 11 July 2008; received in revised form 26 August 2008; accepted 22 September 2008. published online 10 November 2008.
Summary
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 (Vkorc1Y→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 Vkorc1Y→C/Y→C, heterozygous Vkorc1Y→C/+ and wildtype Vkorc1+/+ rats of both sexes.
Results
We observed that the aorta of the heart was mineralized in the Vkorc1Y→C/Y→C male rats but lesions were virtually absent from Vkorc1Y→C/+ and Vkorc1+/+ male and all female rats. The renal arteries were mineralized in Vkorc1Y→C/Y→C and Vkorc1Y→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.
aDepartment of Ecology and Evolutionary Biology, Institute of Biosciences and Bioengineering, Rice University, MS 170, 6100 Main Street, Houston, TX 77005, USA
bComparative Pathology Laboratory, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
cFederal Research Centre for Cultivated Plants, Julius Kuehn Institute, Vertebrate Research, Toppheideweg 88, Münster 48161, Germany
ABSTRACT