Is matrix Gla protein the link between vitamin K and cardiovascular disease risk?

Abstract

We investigated the role of MGP carboxylation (i.e. activation) in the association of high vitamin K intake with reduced vascular calcification and cardiovascular disease risk. We hypothesized that a high vitamin K intake will increase carboxylation of MGP, which will reduce vascular calcification and lower cardiovascular disease risk. Theoretically, low uncarboxylated and high carboxylated MGP concentrations would be associated with reduced calcification risk. However, MGP exists as various species, which differ in their state of phosphorylation and/or carboxylation: phosphorylated carboxylated (p-cMGP), phosphorylated uncarboxylated (p-ucMGP), desphospho-carboxylated MGP (dp-cMGP) and desphospho-uncarboxylated dp-ucMGP (dp-ucMGP). To date, it is possible to measure circulating dp-ucMGP, dp-cMGP and total-ucMGP (t-ucMGP), which is the sum of p-ucMGP and dp-ucMGP. Within this context, we investigated whether these measurable circulating species are associated with vascular calcification or CVD risk. We showed in a double-blind, randomized placebo-controlled trial that vitamin K supplementation decreases circulating dp-ucMGP concentrations. This is confirmed by results of our prospective study in which an association of high dietary vitamin K intake with lower dp-ucMGP concentrations was observed. Therefore circulating dp-ucMGP may serve as biomarker for vitamin K intake. Other MGP species were not associated with vitamin K intake. Based on the effects of vitamin K supplementation on dp-ucMGP, we expected that higher circulating dp-ucMGP concentrations, reflecting low vitamin K intake, would result in a decreased capacity to inhibit calcification. We indeed observed modest associations between high circulating dp-ucMGP concentrations and vascular calcification, both in a cross-sectional and a prospective study. Moreover, in type 2 diabetes patients, a high-risk population, we observed that high circulating dp-ucMGP concentrations were associated with increased cardiovascular disease risk. In contrast, circulating dp-ucMGP concentrations were not associated with coronary heart disease or stroke risk in the general population. We did not find an association between dp-cMGP and vascular calcification or cardiovascular disease risk. In our cross-sectional study we observed that high t-ucMGP concentrations tended to be associated with lower probability of having coronary artery calcification. This association strengthened to a significant association between high t-ucMGP concentrations and lower amount of coronary artery calcification amongst women with coronary artery calcification. Similarly, in our prospective study we observed that high circulating t‑ucMGP concentrations were modestly associated with less calcified areas. Therefore, circulating t-ucMGP might be a biomarker for presence of vascular calcification. Overall, we found that high vitamin K intake decreases circulating dp-ucMGP concentrations and therefore circulating dp-ucMGP may serve as biomarker for vitamin K intake. We observed that increased dp-ucMGP levels were associated with more vascular calcification and increased cardiovascular disease among type 2 diabetes patients. This suggest that dp-ucMGP may form a link between vitamin K and vascular calcification or cardiovascular disease, although we could not confirm this in the general population.