Tissue-specific Utilization of menaquinone-4 Results in the Prevention of Arterial Calcification in Warfarin-Treated Rats

J Vasc Res. Nov-Dec 2003;40(6):531-7. doi: 10.1159/000075344. Epub 2003 Dec 3.

Abstract

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.

MeSH terms

  • Animals
  • Anticoagulants*
  • Antifibrinolytic Agents / pharmacokinetics
  • Aorta / metabolism
  • Aorta / pathology
  • Arteriosclerosis / drug therapy
  • Arteriosclerosis / pathology
  • Arteriosclerosis / prevention & control
  • Calcinosis / drug therapy
  • Calcinosis / pathology
  • Calcinosis / prevention & control*
  • Drug Therapy, Combination
  • Epoxy Compounds / metabolism
  • Hemostatics / pharmacokinetics*
  • Liver / metabolism
  • Male
  • Rats
  • Rats, Inbred WKY
  • Tissue Distribution
  • Vitamin K 1 / pharmacokinetics
  • Vitamin K 2 / analogs & derivatives*
  • Vitamin K 2 / pharmacokinetics*
  • Warfarin*

Substances

  • Anticoagulants
  • Antifibrinolytic Agents
  • Epoxy Compounds
  • Hemostatics
  • Vitamin K 2
  • menatetrenone
  • Warfarin
  • Vitamin K 1