A cardiovascular phenotype in warfarin-resistant Vkorc1 mutant rats☆

Michael H. Kohn; Roger E. Price; Hans-Joachim Pelz

doi:10.1016/j.artres.2008.09.002

<Previous Article In Issue

Next Article In Issue>

Volume 2, Issue 4, November 2008, Pages 138 - 147

A cardiovascular phenotype in warfarin-resistant Vkorc1 mutant rats^☆

Authors

Michael H. Kohn^a^{, *}, Roger E. Price^b, Hans-Joachim Pelz^c

^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

^☆

Grant support: Hamill Innovation grant; and National Heart, Lung, and Blood Institute (NHLBI).

^*Corresponding author. Tel.: +1 713 348 3779; fax: +1 713 348 5232. E-mail address: hmkohn@rice.edu (M.H. Kohn).

Corresponding Author

Michael H. Kohn

Received 11 July 2008, Revised 26 August 2008, Accepted 22 September 2008, Available Online 7 November 2008.

DOI: 10.1016/j.artres.2008.09.002 How to use a DOI?
Keywords: Aorta; Mineralization; Renal artery; Urolith; Vitamin K epoxide reductase; Warfarin
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.
Open Access: This is an open access article distributed under the CC BY-NC license.

Download article (PDF)
View full text (HTML)

<Previous Article In Issue

Next Article In Issue>

Journal: Artery Research
Volume-Issue: 2 - 4
Pages: 138 - 147
Publication Date: 2008/11/07
ISSN (Online): 1876-4401
ISSN (Print): 1872-9312
DOI: 10.1016/j.artres.2008.09.002 How to use a DOI?
Open Access: This is an open access article distributed under the CC BY-NC license.

Cite this article

ris enw bib

TY  - JOUR
AU  - Michael H. Kohn
AU  - Roger E. Price
AU  - Hans-Joachim Pelz
PY  - 2008
DA  - 2008/11/07
TI  - A cardiovascular phenotype in warfarin-resistant Vkorc1 mutant rats☆
JO  - Artery Research
SP  - 138
EP  - 147
VL  - 2
IS  - 4
SN  - 1876-4401
UR  - https://doi.org/10.1016/j.artres.2008.09.002
DO  - 10.1016/j.artres.2008.09.002
ID  - Kohn2008
ER  -

download .riscopy to clipboard