title: Warfarin induces cardiovascular damage in mice.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: From the Department of Nephrology, University Hospital of the Rheinisch Westfälische Technische Hochschule Aachen, Aachen, Germany (T.K., S.O., N.K., P.B., G.S., V.M.B., J.F.); Department of Biochemistry, Cardiovascular Research Institute CARIM, University of Maastricht, Maastricht, The Netherlands (L.J.S.); Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Düsseldorf, Düsseldorf, Germany (A.M.v.d.S., V.V., R.W.); Department of Pathology, University Hospital of the RWTH Aachen, Aachen, Germany (P.B.); Institute of Molecular Biomedicine, Comenius University, Bratislava, Slovakia (P.B.); 2nd Department of Medicine, Military Hospital Budapest, Budapest, Hungary (B.C.F.); Nephrology, Hospital Coburg, Coburg, Germany (M.K.); VitaK BV, Maastricht, The Netherlands (C.V.); Biointerface Laboratory, Helmholtz-Institute of Biomedical Engineering, Aachen, Germany (W.J-D.).
authors.forename: Thilo
authors.initials: T
authors.lastname: Krüger
authors.forename: Stephan
authors.initials: S
authors.lastname: Oelenberg
authors.forename: Nadine
authors.initials: N
authors.lastname: Kaesler
authors.forename: Leon J
authors.initials: LJ
authors.lastname: Schurgers
authors.forename: Annette M
authors.initials: AM
authors.lastname: van de Sandt
authors.forename: Peter
authors.initials: P
authors.lastname: Boor
authors.forename: Georg
authors.initials: G
authors.lastname: Schlieper
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Brandenburg
authors.forename: Bertalan C
authors.initials: BC
authors.lastname: Fekete
authors.forename: Verena
authors.initials: V
authors.lastname: Veulemans
authors.forename: Markus
authors.initials: M
authors.lastname: Ketteler
authors.forename: Cees
authors.initials: C
authors.lastname: Vermeer
authors.forename: Willi
authors.initials: W
authors.lastname: Jahnen-Dechent
authors.forename: Jürgen
authors.initials: J
authors.lastname: Floege
authors.forename: Ralf
authors.initials: R
authors.lastname: Westenfeld
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D000933:Antifibrinolytic Agents / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D011673:Pulsatile Flow / Q000187:drug effects / Q000502:physiology; D012307:Risk Factors; D061205:Vascular Calcification / Q000139:chemically induced* / Q000453:epidemiology / Q000473:pathology*; D010837:Vitamin K 1 / Q000494:pharmacology; D024482:Vitamin K 2 / Q000494:pharmacology; D014859:Warfarin / Q000494:pharmacology*
chemical_list: D000925:Anticoagulants; D000933:Antifibrinolytic Agents; D024482:Vitamin K 2; D014859:Warfarin; D010837:Vitamin K 1; D002118:Calcium
keywords: aortic valve stenosis; matrix Gla protein; pulse-wave velocity; vascular calcification; vitamin K; warfarin