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© 2000 American Heart Association, Inc.
Vascular Biology |
Warfarin-Induced Artery Calcification Is Accelerated by Growth and Vitamin D
From the Department of Biology, University of California, San Diego, La Jolla.
Correspondence to Dr Paul A. Price, Department of Biology, 0368, University of California, San Diego, La Jolla, CA 92093-0368. E-mail pprice{at}ucsd.edu
Abstract—The present studies
demonstrate that growth and vitamin D treatment enhance the extent of
artery calcification in rats given sufficient doses of Warfarin to
inhibit 
-carboxylation of matrix Gla protein, a calcification
inhibitor known to be expressed by smooth muscle cells and
macrophages in the artery wall. The first series of experiments
examined the influence of age and growth status on artery calcification
in Warfarin-treated rats. Treatment for 2 weeks with Warfarin caused
massive focal calcification of the artery media in 20-day-old rats and
less extensive focal calcification in 42-day-old rats. In contrast, no
artery calcification could be detected in 10-month-old adult rats even
after 4 weeks of Warfarin treatment. To directly examine the importance
of growth to Warfarin-induced artery calcification in animals of the
same age, 20-day-old rats were fed for 2 weeks either an ad libitum
diet or a 6-g/d restricted diet that maintains weight but prevents
growth. Concurrent treatment of both dietary groups with Warfarin
produced massive focal calcification of the artery media in the ad
libitum–fed rats but no detectable artery calcification in the
restricted-diet, growth-inhibited group. Although the explanation for
the association between artery calcification and growth status cannot
be determined from the present study, there was a relationship
between higher serum phosphate and susceptibility to artery
calcification, with 30% higher levels of serum phosphate in young, ad
libitum–fed rats compared with either of the groups that was
resistant to Warfarin-induced artery calcification, ie, the
10-month-old rats and the restricted-diet, growth-inhibited young rats.
This observation suggests that increased susceptibility to
Warfarin-induced artery calcification could be related to higher serum
phosphate levels. The second set of experiments examined the
possible synergy between vitamin D and Warfarin in artery
calcification. High doses of vitamin D are known to cause calcification
of the artery media in as little as 3 to 4 days. High doses of the
vitamin K antagonist Warfarin are also known to cause
calcification of the artery media, but at treatment times of 2 weeks or
longer yet not at 1 week. In the current study, we investigated the
synergy between these 2 treatments and found that concurrent Warfarin
administration dramatically increased the extent of calcification in
the media of vitamin D–treated rats at 3 and 4 days. There was a close
parallel between the effect of vitamin D dose on artery calcification
and the effect of vitamin D dose on the elevation of serum calcium,
which suggests that vitamin D may induce artery calcification through
its effect on serum calcium. Because Warfarin treatment had no effect
on the elevation in serum calcium produced by vitamin D, the synergy
between Warfarin and vitamin D is probably best explained by the
hypothesis that Warfarin inhibits the activity of matrix Gla protein as
a calcification inhibitor. High levels of matrix Gla
protein are found at sites of artery calcification in rats treated with
vitamin D plus Warfarin, and chemical analysis showed that the
protein that accumulated was indeed not -carboxylated. These
observations indicate that although the -carboxyglutamate residues
of matrix Gla protein are apparently required for its function as a
calcification inhibitor, they are not required for its
accumulation at calcification sites.
Key Words: Warfarin • vitamin K • vitamin D • artery calcification • matrix Gla protein
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