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 γ-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.

Shearer MJ: Vitamin K. Lancet 1995;345:229–234.
Vermeer C: Gamma-carboxyglutamate-containing proteins and the vitamin K-dependent carboxylase. Biochem J 1990;266:625–636.
Suttie JW: Recent advances in hepatic vitamin K metabolism and function. Hepatology 1987;7:367–376.
Fasco MJ, Hildebrandt EF, Suttie JW: Evidence that warfarin anticoagulant action involves two distinct reductase activities. J Biol Chem 1982;257:11210–11212.
Wallin R, Cain D, Sane DC: Matrix Gla protein synthesis and gamma-carboxylation in the aortic vessel wall and proliferating vascular smooth muscle cells – A cell system which resembles the system in bone cells. Thromb Haemost 1999;82:1764–1767.
Price PA, Williamson MK, Haba T, Dell RB, Jee WS: Excessive mineralization with growth plate closure in rats on chronic warfarin treatment. Proc Natl Acad Sci USA 1982;79:7734–7738.
Price PA, Faus SA, Williamson MK: Warfarin causes rapid calcification of the elastic lamellae in rat arteries and heart valves. Arterioscler Thromb Vasc Biol 1998;18:1400–1407.
Price PA, Kaneda Y: Vitamin K counteracts the effect of warfarin in liver but not in bone. Thromb Res 1987;46:121–131.
Price PA, Faus SA, Williamson MK: Warfarin-induced artery calcification is accelerated by growth and vitamin D. Arterioscler Thromb Vasc Biol 2000;20:317–327.
Ronden JE, Drittij-Reijnders MJ, Vermeer C, Thijssen HHW: Intestinal flora is not an intermediate in the phylloquinone-menaquinone-4 conversion in the rat. Biochim Biophys Acta 1998;1379:69–75.
Gelijnse JM, Vermeer C, Schurgers LJ, Grobbee DE, Pols HAP, Witteman JCM: Inverse association of dietary vitamin K-2 intake with cardiac events and aortic atherosclerosis: The Rotterdam Study. Abstracts of XVIIIth ISTH Congress. Thromb Haemost 2001, p 473.
Price PA, Faus SA, Williamson MK: Bisphosphonates alendronate and ibandronate inhibit artery calcification at doses comparable to those that inhibit bone resorption. Arterioscler Thromb Vasc Biol 2001;21:817–824.
Thijssen HHW, Drittij Reijnders MJ: Vitamin K distribution in rat tissues: Dietary phylloquinone is a source of tissue menaquinone-4. Br J Nutr 1994;72:415–425.
Haroon Y, Bacon DS, Sadowski JA: Chemical reduction system for the detection of phylloquinone (vitamin K1) and menaquinones (vitamin K2). J Chromatogr 1987;384:383–389.
Thijssen HHW, Drittij Reijnders MJ, Fischer MA: Phylloquinone and menaquinone-4 distribution in rats: Synthesis rather than uptake determines menaquinone-4 organ concentrations. J Nutr 1996;126:537–543.
Kindberg CG, Suttie JW: Effect of various intakes of phylloquinone on signs of vitamin K deficiency and serum and liver phylloquinone concentrations in the rat. J Nutr 1989;119:175–180.
Groenen-van Dooren MMCL, Soute BAM, Jie KS, Thijssen HHW, Vermeer C: The relative effects of phylloquinone and menaquinone-4 on the blood coagulation factor synthesis in vitamin K-deficient rats. Biochem Pharmacol 1993;46:433–437.
Ronden JE, Thijssen HHW, Vermeer C: Tissue distribution of K-vitamers under different nutritional regimens in the rat. Biochim Biophys Acta 1998;1379:16–22.
Schurgers LJ, Vermeer C: Differential lipoprotein transport pathways of K-vitamins in healthy subjects. Biochim Biophys Acta 2002;1570:27–32.
Buitenhuis HC, Soute BA, Vermeer C: Comparison of the vitamins K1, K2 and K3 as cofactors for the hepatic vitamin K-dependent carboxylase. Biochim Biophys Acta 1990;1034:170–175.
Reedstrom CK, Suttie JW: Comparative distribution, metabolism, and utilization of phylloquinone and menaquinone-9 in rat liver. Proc Soc Exp Biol Med 1995;209:403–409.
Orimo H, Shiraki M, Tomita A, Morii H, Fujita T, Ohata M: Effects of menatetrenone on the bone and calcium metabolism in osteoporosis: A double-blind placebo-controlled study. J Bone Miner Metab 1998;16:106–112.
Akiba T, Kurihara S, Tachibana K, Kuwahara M, Sakamoto H, Yoneshima H, Marumo F: Vitamin K (K) increased bone mass (BM) in hemodialysis patients (Pts) with low-turnover bone disease (LTOBD). J Am Soc Nephrol 1991;2:608.
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