Vascular Calcification in Chronic Kidney Disease: The Role of Vitamin K- Dependent Matrix Gla Protein

Stefanos Roumeliotis, Evangelia Dounousi, Marios Salmas, Theodoros Eleftheriadis, Vassilios Liakopoulos, Stefanos Roumeliotis, Evangelia Dounousi, Marios Salmas, Theodoros Eleftheriadis, Vassilios Liakopoulos

Abstract

Arterial calcification is highly prevalent in chronic kidney disease (CKD) patients and is associated with cardiovascular (CV) morbidity and mortality. Patients at early CKD stages are more likely to suffer a fatal CV event than to develop end-stage renal disease and require hemodialysis treatment. The heavy CV burden of these patients cannot be solely explained by traditional calcification risk factors. Moreover, the pathophysiologic mechanisms underlying this association are complex and yet not fully understood. Although vascular calcification was regarded as a passive degenerative process for over a century, this theory changed by recent evidence that pointed toward an active process, where calcification promoters and inhibitors were involved. Matrix Gla Protein (MGP) has been established as a strong inhibitor of calcification both in vitro and in vivo. Not only it prevents mineralization of the arterial wall, but it is the only factor that can actually reverse it. To become fully active, MGP must undergo carboxylation of specific protein bound glutamate residues, a process fully dependent on the availability of vitamin K. Low vitamin K status leads to inactive, uncarboxylated forms of MGP and has been repeatedly associated with accelerated vascular calcification. Aim of this review is to present the pathophysiologic mechanisms underlying the activation and function of MGP and review the existing, accumulating data regarding the association between vitamin K, MGP and vascular calcification/CV disease in CKD patients.

Keywords: Matrix Gla protein; chronic kidney disease; dephosphorylated uncarboxylated Matrix Gla protein; end-stage renal disease; vascular calcification; vitamin K; vitamin K-dependent protein.

Copyright © 2020 Roumeliotis, Dounousi, Salmas, Eleftheriadis and Liakopoulos.

Figures

Figure 1
Figure 1
Activation/inactivation processes of Matrix Gla Protein. Dp-ucMGP is the fully inactive form of MGP. If vitamin K is deficient, MGP remains in its inactive form and favors arterial calcification or stiffness, atherosclerosis and subsequent cardiovascular disease. In states of high vitamin K, dp-ucMGP undergoes γ-carboxylation of its glutamate residues and transforms to the cMGP form. In turn, using vitamin K as co-factor, cMGP undergoes phosphorylation of its serine residues and become the fully activated pcMGP. Only in this form, MGP abrogates the connection of BMP-2 to its receptor, tightly binds to free calcium and hydroxyapatite crystals to from inactive complexes and activates autophagic clearance of these complexes by attracting phagocytes and macrophages. MGP, Matrix Gla Protein; dp-ucMGP, dephoshorylated uncarboxylated MGP; cMGP, carboxylated MGP; pcMGP, phosphorylated carboxylated MGP; Ca++, calcium anions; BMP, Bone Morphogenetic Protein.

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