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      Tissue-Specific Utilization of Menaquinone-4 Results in the Prevention of Arterial Calcification in Warfarin-Treated Rats

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          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.

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          Most cited references 5

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          Vitamin K

           M.J. Shearer (1995)
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            Effects of menatetrenone on the bone and calcium metabolism in osteoporosis: A double-blind placebo-controlled study

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              Vitamin K counteracts the effect of warfarin in liver but not in bone.

              Treatment with high dosages of Vitamin K completely inhibited the effect of Warfarin on blood coagulation but had essentially no ability to counteract the effect of Warfarin on the gamma-carboxylation of bone G1a protein (BGP; osteocalcin). Provided that rats received the appropriate dosage of Vitamin K prior to and concurrent with the administration of Warfarin, daily dosages as high as 7.7 mg Warfarin per 100 g body weight had no effect on blood coagulation times. This Warfarin dosage is approximately 150 times higher than the 50 micrograms per 100 g body weight which caused coagulation times to double in rats which did not receive Vitamin K. In dramatic contrast, the dosage of Warfarin required to reduce the gamma-carboxylation status of BGP to one-half normal, 30 micrograms per 100 g body weight, was essentially unaffected by Vitamin K treatment. These results indicate the existence of a major difference between the metabolism of Vitamin K by the hepatocytes which synthesize coagulation factors and the osteoblasts which synthesize BGP. The practical consequence of this difference is that it is now possible to antagonize the action of Vitamin K in osteoblasts, as well as in other cells which have the same Vitamin K metabolism, without affecting blood coagulation times.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                December 2003
                29 January 2004
                : 40
                : 6
                : 531-537
                Departments of aBiochemistry, bInternal Medicine, and cPharmacology, Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht, The Netherlands
                75344 J Vasc Res 2003;40:531–537
                © 2003 S. Karger AG, Basel

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                Page count
                Figures: 1, Tables: 2, References: 23, Pages: 7
                Research Paper


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