Vitamin K-dependent proteins, warfarin, and vascular calcification

Abstract

Vitamin K-dependent proteins (VKDPs) require carboxylation to become biologically active. Although the coagulant factors are the most well-known VKDPs, there are many others with important physiologic roles. Matrix Gla Protein (MGP) and Growth Arrest Specific Gene 6 (Gas-6) are two particularly important VKDPs, and their roles in vascular biology are just beginning to be understood. Both function to protect the vasculature; MGP prevents vascular calcification and Gas-6 affects vascular smooth muscle cell apoptosis and movement. Unlike the coagulant factors, which undergo hepatic carboxylation, MGP and Gas-6 are carboxylated within the vasculature. This peripheral carboxylation process is distinct from hepatic carboxylation, yet both are inhibited by warfarin administration. Warfarin prevents the activation of MGP and Gas-6, and in animals, induces vascular calcification. The relationship of warfarin to vascular calcification in humans is not fully known, yet observational data suggest an association. Given the high risk of vascular calcification in those patients with chronic kidney disease, the importance of understanding warfarin's effect on VKDPs is paramount. Furthermore, recognizing the importance of VKDPs in vascular biology will stimulate new areas of research and offer potential therapeutic interventions.

Figure 1.

Hepatic and peripheral carboxylation of VKDPs. Vitamin K-dependent proteins undergo carboxylation to become biologically active, requiring vitamin K as a cofactor in the conversion. In hepatic carboxylation, the liver uses vitamin K1 to activate the coagulation factors. In a distinct process, vascular smooth muscle cells produce and activate MGP and Gas-6, two proteins with important roles in vascular biology, affecting cell movement, survival, and calcification. This peripheral carboxylation primarily depends on a family of menaquinones, collectively known as vitamin K2, which differ in structure and metabolism from vitamin K1. Vitamin K1 predominantly is derived from the diet. Vitamin K2 comes either from enterocyte conversion of vitamin K1 or from indigenous intestinal bacteria production.

Figure 2.

Warfarin inhibits hepatic and peripheral carboxylation. Warfarin prevents vitamin K from participating in the carboxylation process, inhibiting both hepatic and peripheral production of VKDPs. The well-known therapeutic effect is anticoagulation. However, warfarin also inhibits activation of MGP and Gas-6, interrupting the protective mechanisms of these proteins. Vascular smooth muscle cells are unable to respond to injury in a normal manner, and potentially, cell death and eventual calcification ensue. Deficiency of vitamin K2, resulting from either vitamin K1 nutritional deficiency, malabsorptive states, or alteration of indigenous intestinal flora, may potentially lead to vascular injury.