http://atvb.ahajournals.org/content/33/11/2618.abstract.html?etoc
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.
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.
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