Vitamin k dependent proteins and the role of vitamin k2 in the modulation of vascular calcification: a review

Abstract

Vascular calcification, a cause of cardiovascular morbidity and mortality, is an actively regulated process involving vitamin K dependent proteins (VKDPs) among others. Vitamin K is an essential micronutrient, present in plants and animal fermented products that plays an important role as a cofactor for the post-translational γ-carboxylation of glutamic acid residues in a number of proteins. These VKDPs require carboxylation to become biologically active, and they have been identified as having an active role in vascular cell migration, angiogenesis and vascular calcification. This paper will review the process of vascular calcification and delineate the role that vitamin K2 plays in the modulation of that process, through the activation of VKDPs. One such VKDP is Matrix Gla Protein (MGP), which when activated inhibits osteogenic factors, thereby inhibiting vascular and soft tissue calcification.

Keywords: Matrix glutamate-Protein (MGP); Menaquinone; Vascular Calcification; Vitamin K; Vitamin K antagonists; Vitamin K2; Warfarin.

Figure 2

Vitamin K carboxylation cycle. The oxidation of the hydroquinone form is coupled to the carboxylation of Vitamin K dependent proteins (VKDPs). Vitamin K can be reduced into its hydroquinone form through the action of two enzymes; one of these is sensitive to the action of vitamin K antagonists (VKA) such as warfarin, while the other is not. However, the reduction of vitamin K epoxide can only be achieved by an enzyme sensitive to VKA. This cycle is coupled to the carboxylation of glutamic acid residues in proteins. VKOR: Vitamin K epoxide reductase; ucVKDP: under-carboxylated VKDP; cVKDP: carboxylated VKDP; Glu: glutamic acid; Gla: γ-carboxyglutamic acid.

Figure 1

The chemical structures of vitamin K. Vitamin K₂ represents a group of molecules with a varying number of isoprene units. Each molecule can be named as mk-n, which represents the number of isoprene units it contains.

Figure 3

The process of vascular calcification. Mineralization of the ECM induces an increase in the expression of MGP as a negative feedback mechanism. The up-regulation of MGP causes a relative deficiency in vitamin K which, if not replenished, will lead to inactive MGP and vascular calcification. A decrease in the expression of calcification inhibitors such as OPN, Osteopontin; PPi, pyrophosphate; BMP-2 and BMP-4, Bone Morphogenetic Protein-2 and 4, resepctively, may also result in vascular calcification.

Figure 4

The effect of vitamin K on MGP and vascular calcification. Different species of MGP are affected by the presence of vitamin K. These include Dp-cMGP, non-phosphorylated carboxylated MGP; p-cMGP, phosphorylated MGP; p-ucMGP, phosphorylated-non-carboxylated MGP; dp-ucMGP, non-phosphorylated non-carboxylated MGP.