Warfarin Induces Cardiovascular Damage in Mice

Thilo Krueger*, Stephan Oelenberg, Nadine Kaesler, Leon J. Schurgers, Annette M. van de Sandt, Peter Boor, Georg Schlieper, Vincent M. Brandenburg, Bertalan C. Fekete, Verena Veulemans, Markus Ketteler, Cees Vermeer, Willi Jahnen-Dechent, Juergen Floege, Ralf Westenfeld

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Objective Vascular calcification is an independent risk factor for cardiovascular disease. Once thought to be a passive process, vascular calcification is now known to be actively prevented by proteins acting systemically (fetuin-A) or locally (matrix Gla protein). Warfarin is a vitamin K antagonist, widely prescribed to reduce coagulation by inhibiting vitamin K-dependent coagulation factors. Recently, it became clear that vitamin K antagonists also affect vascular calcification by inactivation of matrix Gla protein. Here, we investigated functional cardiovascular characteristics in a mouse model with warfarin-induced media calcification. Approach and Results DBA/2 mice received diets with variable concentrations of warfarin (0.03, 0.3, and 3 mg/g) with vitamin K1 at variable time intervals (1, 4, and 7 weeks). Von Kossa staining revealed that warfarin treatment induced calcified areas in both medial layer of aorta and heart in a dose- and time-dependent fashion, which could be inhibited by simultaneous vitamin K2 treatment. With ongoing calcification, matrix Gla protein mRNA expression decreased, and inactive matrix Gla protein expression increased. TdT-mediated dUTP-biotin nick end labeling-positive apoptosis increased, and vascular smooth muscle cell number was concomitantly reduced by warfarin treatment. On a functional level, warfarin treatment augmented aortic peak velocity, aortic valve-peak gradient, and carotid pulse-wave velocity. Conclusion Warfarin induced significant calcification with resulting functional cardiovascular damage in DBA/2 wild-type mice. The model would enable future researchers to decipher mechanisms of vascular calcification and may guide them in the development of new therapeutic strategies.
Original languageEnglish
Pages (from-to)2618-2624
JournalArteriosclerosis Thrombosis and Vascular Biology
Issue number11
Publication statusPublished - Nov 2013


  • aortic valve stenosis
  • matrix Gla protein
  • pulse-wave velocity
  • vascular calcification
  • vitamin K
  • warfarin

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