Matrix Gla-protein: The calcification inhibitor in need of vitamin K

VitaK, Maastricht University, Universiteitssingel 50, Maastricht, The Netherlands.
Thrombosis and Haemostasis (Impact Factor: 5.76). 11/2008; 100(4):593-603. DOI: 10.1160/TH08-02-0087
Source: PubMed

ABSTRACT Among the proteins involved in vascular calcium metabolism, the vitamin K-dependent matrix Gla-protein (MGP) plays a dominant role. Although on a molecular level its mechanism of action is not completely understood, it is generally accepted that MGP is a potent inhibitor of arterial calcification. Its pivotal importance for vascular health is demonstrated by the fact that there seems to be no effective alternative mechanism for calcification inhibition in the vasculature. An optimal vitamin K intake is therefore important to maintain the risk and rate of calcification as low as possible. With the aid of conformation-specific antibodies MGP species in both tissue and the circulation have been detected in the healthy population, and significant differences were found in patients with cardiovascular disease (CVD). Using ELISA-based assays, uncarboxylated MGP (ucMGP) was demonstrated to be a promising biomarker for cardiovascular calcification detection. These assays may have potential value for identifying patients as well as apparently healthy subjects at high risk for CVD and/or cardiovascular calcification and for monitoring the treatment of CVD and vascular calcification.

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Available from: Leon J Schurgers, Aug 26, 2015
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    • "En effet, plusieurs e ´ tudes ont dé montré que les concentrations de dp-ucMGP augmentent significativement chez les patients traité s par anti-vitamine K (AVK) [27,36,44–47] et, inversement, diminuent aprè s initiation d'un traitement par vitamine K, y compris dans le contexte de la maladie ré nale chronique (MRC) [27] [36] [46] [48]. Certaines donné es, nous y reviendrons, suggè rent une association positive entre les concentrations de dp-ucMGP et l'intensité des calcifications vasculaires (plus il y a de MGP inactive, plus il y a de risque de calcifications). "
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    ABSTRACT: Matrix-gla-protein (MGP) is mainly secreted by chondrocytes and smooth vascular muscle cells. This potent inhibitor of vascular calcification need to undergo 2 post-transcriptional steps to be fully active: one phosphorylation of 3 serine residues (on 5) and a carboxylation of 5 glutamate residues (on 9). Like other "Gla" proteins, this carboxylation is vitamin K dependant. Several forms of MGP thus circulate in the plasma, some of them being totally inactive (the unphosphorylated and uncarboxylated MGP), some others being partially or fully active, according to the number of phosphorylated or carboxylated sites. A theoretical link exists between MGP, vitamin K, vascular calcifications and cardiovascular diseases. This link is even more evident in patients suffering from chronic kidney diseases (CKD), and notably hemodialysis patients. If this link has been demonstrated in different experimental studies, clinical studies are mainly observational and their results must be interpreted accordingly. MGP concentrations are definitely not yet a surrogate to estimate the levels of vascular calcification, but could allow the monitoring of vitamin K treatment. Modulation of MGP concentrations may reduce vascular calcification in hemodialyzed patients, if the large ongoing trials show an efficiency of this treatment. In this review, we will summarize the role of MGP in the vascular calcifications process, describe the problems linked to the analytical determination of MGP in plasma and finally describe the different clinical studies on MGP and vascular calcifications in the general population and in CKD patients. Copyright © 2015 Association Société de néphrologie. Published by Elsevier SAS. All rights reserved.
    Néphrologie & Thérapeutique 03/2015; DOI:10.1016/j.nephro.2014.12.003 · 0.55 Impact Factor
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    • "Even if MMP-9 was also decreased, statistical significance was not reached. MMP-9 is localized in VSMCs (Woodside et al 2003) which also represent the site of MGP synthesis (Schurgers et al 2008). It seems possible that these findings could be the consequence of the surgical removal of VV, resulting in a decrease of venous tissue and therefore of VSMCs. "
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    ABSTRACT: Objectives: The main objective was to assess the interplay between circulating matrix Gla protein (MGP) - marker for vascular calcification, matrix metalloproteinase-9 (MMP-9) - marker for extracellular matrix remodeling and nitrotyrosine (NT) - marker for oxidative stress in patients with varicose veins (VV). Moreover, we wanted to investigate the behavior of these parameters before and after a stressful event (surgical removal of VV from lower limbs) and to find out if there is a contribution of MGP originating from superficial veins of the lower limb to the total pool of circulating MGP. Material and method: The pilot cohort study was accomplished on patients with VV (n=29) before and after a stressful event (surgical removal of VV from inferior limbs) and a group of age-gender matched apparently healthy volunteers (n=29). Plasma levels of tMGP, MMP-9 and NT were assayed with commercially available immunoassay kits. Results: Differences between patients with VV and age-sex matched healthy subjects were reflected only by higher levels of MMP-9 [82 (19-159) ng/mL versus 36 (2-108) ng/mL, p<0.05]; and not by circulating tMGP or NT levels. When patients before removal of VV were compared to patients after surgery, only tMGP was found significantly decreased [65 (32-97) μg/L versus 40 (17-95) μg/L, p<0.05]. We also found a correlation between tMGP and MMP-9 in patients with VV (r = 0.37, p<0.05). We did not find any correlation of NT with tMGP or MMP-9 and no significant differences in plasma NT levels in any pairwise comparisons. Conclusion: Higher circulating levels of MMP-9 could differentiate between healthy individuals and patients with chronic venous insufficiency. Consequently, oxidative stress assessed by NT did not affect circulating levels of tMGP or MMP-9 after surgical removal of VV. The constitutive decrease in plasma level of tMGP could be considered the contribution of MGP from superficial veins of the inferior limb to the total pool of circulating MGP
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    • "Plasma dephospho-ucMGP is a marker of vascular calcification in chronic kidney disease [37] [38] and is associated with low VK levels [38] [39] [40]. Thus, VK deficiency accelerates calcification and inhibits coagulation [28], and optimal VK intake is important in order to reduce the risk of occurrence of these diseases [28]. "
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    ABSTRACT: Canola oil (Can) and hydrogenated soybean oil (H2-Soy) are commonly used edible oils. However, in contrast to soybean oil (Soy), they shorten the survival of stroke-prone spontaneously hypertensive (SHRSP) rats. It has been proposed that the adverse effects of these oils on the kidney and testis are caused at least in part by dihydro-vitamin K (VK) 1 in H2-Soy and unidentified component(s) in Can. Increased intake of dihydro-VK1 is associated with decreased tissue VK2 levels and bone mineral density in rats and humans, respectively. The aim of the present study was to determine the effects of these oils on bone morphogenetic protein (BMP)-induced ectopic bone formation, which is promoted by VK2 deficiency, in relation to the role of VK in the γ-carboxylation of osteocalcin and matrix Gla protein. A crude extract of BMPs was implanted into a gap in the fascia of the femoral muscle in 5-week-old mice maintained on a Soy, Can, or H2-Soy diet. Newly formed bone volume, assessed by three-dimensional X-ray micro-computed tomography and three-dimensional reconstruction imaging for bone, was 4-fold greater in the Can and H2-Soy groups than in the Soy group. The plasma carboxylated osteocalcin (Gla-OC) and total OC (Gla-OC plus undercarboxylated osteocalcin [Glu-OC]) levels were significantly lower in the Can group than in the Soy group (p < 0.05). However, these levels did not significantly differ between the H2-Soy and Soy groups. The plasma Gla-OC/Glu-OC ratio in the Can and H2-Soy groups was significantly lower (in Can; p = 0.044) or was almost significantly lower (in H2-Soy; p = 0.053) than that in the Soy group. In conclusion, Can and H2-Soy accelerated BMP-induced bone formation in mice to a greater extent than Soy. Further research is required to evaluate whether the difference in accelerated ectopic bone formation is associated with altered levels of VK2 and VK-dependent protein(s) among the three dietary groups.
    Toxicology Reports 11/2014; 1. DOI:10.1016/j.toxrep.2014.10.021
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