Tissue-specific utilization of menaquinone-4 results in the prevention of arterial calcification in warfarin-treated rats.
The effects of vitamin K (phylloquinone: K1 and menaquinone-4: MK-4) on vascular calcification and their utilization in the arterial vessel wall were compared in the warfarin-treated rat model for arterial calcification. Warfarin-treated rats were fed diets containing K1, MK-4, or both. Both K1 and MK-4 are cofactors for the endoplasmic reticulum enzyme gamma-glutamyl carboxylase but have a structurally different aliphatic side chain. Despite their similar in vitro cofactor activity we show that MK-4 and not K1 inhibits warfarin-induced arterial calcification. The total hepatic K1 accumulation was threefold higher than that of MK-4, whereas aortic MK-4 was three times that of K1. The utilization of K1 and MK-4 in various tissues was estimated by calculating the ratios between accumulated quinone and epoxide species. K1 and MK-4 were both equally utilized in the liver, but the aorta showed a more efficient utilization of MK-4. Therefore, the observed differences between K1 and MK-4 with respect to inhibition of arterial calcification may be explained by both differences in their tissue bioavailability and cofactor utilization in the reductase/carboxylase reaction. An alternative explanation may come from an as yet hypothetical function of the geranylgeranyl side chain of MK-4, which is a structural analogue of geranylgeranyl pyrophosphate and could interfere with a critical step in the mevalonate pathway.
Spronk
H M H
HM
Department of Biochemistry, Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, The Netherlands. henri.spronk@bioch.unimaas.nl
Soute
B A M
BA
Schurgers
L J
LJ
Thijssen
H H W
HH
De Mey
J G R
JG
Vermeer
C
C
D000818:Animals; D000925:Anticoagulants; D000933:Antifibrinolytic Agents / Q000493:pharmacokinetics; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001161:Arteriosclerosis / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control; D002114:Calcinosis / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D004359:Drug Therapy, Combination; D004852:Epoxy Compounds / Q000378:metabolism; D006490:Hemostatics / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism; D008297:Male; D051381:Rats; D011921:Rats, Inbred WKY; D014018:Tissue Distribution; D010837:Vitamin K 1 / Q000493:pharmacokinetics; D024482:Vitamin K 2 / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D014859:Warfarin
D000925:Anticoagulants; D000933:Antifibrinolytic Agents; D004852:Epoxy Compounds; D006490:Hemostatics; D024482:Vitamin K 2; C030814:menatetrenone; D014859:Warfarin; D010837:Vitamin K 1