Matrix-GLA-Protein and Vascular Calcification: Can Diet Influence the Consequences of Matrix GLA Protein Inactivation? A Review

In vascular calcification, as a physiological process, intimal arterial calcification (IAC) associated with increased cardiovascular risk is distinguished from medial arterial calcification (MAC) localized mainly in the lamina elatica interna, which are not only based on different pathophysiological mechanisms. They also lead to different cardiovascular diseases. While intimal arterial calcification involves inflammation and lipid accumulation, a calcification process similar to desmal ossification plays the main role in medial arterial calcification. In this context, the phenotype change of smooth muscle cells from muscular type to synthesizing form in the tunica media is considered to be of great importance, which puts the matrix GLA protein, mainly involved in bone metabolism, in the center of interest. The present review work elucidates the molecular biological basis of interaction of matrix GLA protein subunits in the pathogenesis of vascular calcifications and the influence of diet on the consequences of underactivation of matrix GLA protein.

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Association of genetic polymorphisms in the Matrix Gla Protein (MGP) gene with coronary artery disease and serum mgp levels

Balkan Journal of Medical Genetics ◽

10.2478/bjmg-2019-0020 ◽

2019 ◽

Vol 22 (2) ◽

pp. 43-50

Author(s):

S Karsli-Ceppioglu ◽

S Yazar ◽

Y Keskin ◽

M Karaca ◽

NE Luleci ◽

...

Keyword(s):

Coronary Artery ◽

Gene Polymorphisms ◽

Regulatory Protein ◽

Matrix Gla Protein ◽

Arterial Calcification ◽

Coronary Artery Diseases ◽

Related Gene ◽

The Matrix ◽

Artery Disease

AbstractMatrix Gla protein (MGP) is an important regulatory protein for inhibition of calcification in the vessel wall and cartilage. The MGP gene polymorphisms are suspected to increase the risk of extracellular calcification through altering the related gene expression and serum MGP levels. The goal of this study was to examine the correlation between rs4236 (Thr83-Ala), rs12304 (Glu60-X) and rs1800802 (T138-C) polymorphisms of the MGP gene and coronary artery calcification. Serum MGP levels of 168 subjects who had undergone coronary angiography were analyzed along with genotyping of MGP gene polymorphisms. The results indicated that serum MGP levels were significantly associated with rs4236 and rs1800802 polymorphisms of the MGP gene with the occurrence of coronary artery diseases (CAD). Allelic distributions of MGP gene polymorphisms and serum MGP levels, respectively, were not significantly interconnected with the presence of CAD. Our results revealed that serum MGP levels of CAD patients show association with rs4236 and rs1800802 polymorphisms, but serum MGP levels alone do not directly reflect the risk of CAD. The role of MGP genetic variants on formation and progression of arterial calcification should be regarded in cardiovascular diseases.

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The effect of menaquinone-7 supplementation on vascular calcification in patients with diabetes: a randomized, double-blind, placebo-controlled trial

American Journal of Clinical Nutrition ◽

10.1093/ajcn/nqz147 ◽

2019 ◽

Vol 110 (4) ◽

pp. 883-890 ◽

Cited By ~ 18

Author(s):

S R Zwakenberg ◽

P A de Jong ◽

J W Bartstra ◽

R van Asperen ◽

J Westerink ◽

...

Keyword(s):

Type 2 Diabetes ◽

Vascular Calcification ◽

Vitamin K ◽

Controlled Trial ◽

Matrix Gla Protein ◽

Arterial Calcification ◽

Secondary Outcome ◽

Double Blind

ABSTRACT Background Vitamin K occurs in the diet as phylloquinone and menaquinones. Observational studies have shown that both phylloquinone and menaquinone intake might reduce cardiovascular disease (CVD) risk. However, the effect of vitamin K on vascular calcification is unknown. Objectives The aim of this study was to assess if menaquinone supplementation, compared to placebo, decreases vascular calcification in people with type 2 diabetes and known CVD. Methods In this double-blind, randomized, placebo-controlled trial, we randomly assigned men and women with type 2 diabetes and CVD to 360 µg/d menaquinone-7 (MK-7) or placebo for 6 mo. Femoral arterial calcification at baseline and 6 mo was measured with 18sodium fluoride positron emission tomography (18F-NaF PET) scans as target-to-background ratios (TBRs), a promising technique to detect active calcification. Calcification mass on conventional computed tomography (CT) scan was measured as secondary outcome. Dephosphorylated–uncarboxylated matrix Gla protein (dp-ucMGP) concentrations were measured to assess compliance. Linear regression analyses were performed with either TBR or CT calcification at follow-up as the dependent variable, and treatment and baseline TBR or CT calcification as independent variables. Results We randomly assigned 35 patients to the MK-7 group (33 completed follow-up) and 33 to the placebo group (27 completed follow-up). After the 6-mo intervention, TBR tended to increase in the MK-7 group compared with placebo (0.25; 95% CI: −0.02, 0.51; P = 0.06), although this was not significant. Log-transformed CT calcification mass did not increase in the intervention group compared with placebo (0.50; 95% CI: −0.23, 1.36; P = 0.18). MK-7 supplementation significantly reduced dp-ucMGP compared with placebo (−205.6 pmol/L; 95% CI: −255.8, −155.3 pmol/L). No adverse events were reported. Conclusion MK-7 supplementation tended to increase active calcification measured with 18F-NaF PET activity compared with placebo, but no effect was found on conventional CT. Additional research investigating the interpretation of 18F-NaF PET activity is necessary. This trial was registered at clinicaltrials.gov as NCT02839044.

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Matrix Gla protein is associated with coronary artery calcification as assessed by electron-beam computed tomography

Thrombosis and Haemostasis ◽

10.1160/th03-08-0572 ◽

2004 ◽

Vol 91 (04) ◽

pp. 790-794 ◽

Cited By ~ 88

Author(s):

Yuji Ikari ◽

Cees Vermeer ◽

Paul Dissel ◽

Kotaro Hasegawa ◽

Atsushi Shioi ◽

...

Keyword(s):

Computed Tomography ◽

Electron Beam ◽

Coronary Artery ◽

Vascular Calcification ◽

Coronary Artery Calcification ◽

Matrix Gla Protein ◽

Arterial Calcification ◽

Enzyme Linked Immunosorbent Assay ◽

Electron Beam Computed Tomography ◽

Increased Risk

SummaryMatrix Gla protein (MGP) is an extracellular matrix protein with wide tissue distribution. It has been demonstrated that the expression of MGP is detected not only in the normal blood vessels but also calcified atherosclerotic plaques, and that MGP deficient mice develop extensive arterial calcification. MGP is thought to be a regulator of vascular calcification. A recent clinical study demonstrates the association between polymorphisms of the MGP gene and increased risk of myocardial infarction. However, there are no reports of the relationship between serum MGP levels and coronary artery calcification (CAC). We evaluated the severity of CAC using electron-beam computed tomography (EBCT), and measured serum MGP levels by enzyme-linked immunosorbent assay in 115 subjects with suspected coronary artery disease. CAC scores were correlated with traditional risk factors, such as age, gender, hypertension, diabetes, hyperlipidemia and smoking. The serum MGP levels were lower in patients with CAC than in those without CAC (p<0.001). As the severity of CAC increased, there was a significant decrease in serum MGP levels. Serum MGP levels (U/L) were 116.7 ± 20.3, 104.9 ± 19.2, 95.2 ± 15.2 and 82.2 ± 19.7, (medians 115.5, 105.0, 94.8, and 81.9) for the subjects with normal (CAC score=0), mild (CAC score=1 to 99), moderate (CAC score=100 to 400), and severe (CAC score >400) coronary calcification, respectively. We found that serum MGP levels are inversely correlated with the severity of CAC. These data suggest a possible role for MGP in the development of vascular calcification.

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Vitamin K Supplementation for the Prevention of Cardiovascular Disease: Where Is the Evidence? A Systematic Review of Controlled Trials

Nutrients ◽

10.3390/nu12102909 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2909

Author(s):

Caitlyn Vlasschaert ◽

Chloe J. Goss ◽

Nathan G. Pilkey ◽

Sandra McKeown ◽

Rachel M. Holden

Keyword(s):

Systematic Review ◽

Cardiovascular Disease ◽

Vascular Calcification ◽

Vitamin K ◽

Cochrane Collaboration ◽

Matrix Gla Protein ◽

Arterial Calcification ◽

Current Evidence ◽

Controlled Trials ◽

Cochrane Central Register

Matrix gla protein (MGP) is an important vitamin K-dependent inhibitor of vascular calcification. High levels of uncarboxylated, dephosphorylated MGP have been associated with vascular calcification and are responsive to vitamin K treatment. In this systematic review, we summarize the available evidence examining whether vitamin K supplementation improves surrogate measures of cardiovascular disease including artery and valve calcification, atherosclerosis and artery stiffening. Data from controlled trials of adults were obtained by searching Ovid MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and the Web of Science Core Collection. We identified nine randomized controlled trials for review, including trials of vitamin K1 or vitamin K2 supplementation, that assessed a surrogate measure of cardiovascular disease including arterial calcification, atherosclerosis or arterial stiffening. For each trial, the risk of bias was assessed applying Cochrane Collaboration methodology. The findings indicate that vitamin K does not consistently prevent progression of calcification, atherosclerosis or arterial stiffness. There may be some benefit in people with calcification at study entry. Studies were heterogenous, with relatively short follow-up and outcome measures were varied. While vitamin K supplementation clearly improves the carboxylation of dephosphoylated MGP, its role in mitigating vascular calcification is uncertain, based on current evidence.

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Inactivation of the Osteopontin Gene Enhances Vascular Calcification of Matrix Gla Protein–deficient Mice

Journal of Experimental Medicine ◽

10.1084/jem.20020911 ◽

2002 ◽

Vol 196 (8) ◽

pp. 1047-1055 ◽

Cited By ~ 224

Author(s):

Mei Y. Speer ◽

Marc D. McKee ◽

Robert E. Guldberg ◽

Lucy Liaw ◽

Hsueh-Ying Yang ◽

...

Keyword(s):

Vascular Calcification ◽

Dry Weight ◽

Inhibitory Effect ◽

Matrix Gla Protein ◽

Mutant Mice ◽

Arterial Calcification ◽

Ectopic Calcification ◽

Lineage Markers

Osteopontin (OPN) is abundantly expressed in human calcified arteries. To examine the role of OPN in vascular calcification, OPN mutant mice were crossed with matrix Gla protein (MGP) mutant mice. Mice deficient in MGP alone (MGP−/− OPN+/+) showed calcification of their arteries as early as 2 weeks (wk) after birth (0.33 ± 0.01 mmol/g dry weight), and the expression of OPN in the calcified arteries was greatly up-regulated compared with MGP wild-types. OPN accumulated adjacent to the mineral and colocalized to surrounding cells in the calcified media. Cells synthesizing OPN lacked smooth muscle (SM) lineage markers, SM α-actin and SM22α. However, most of them were not macrophages. Importantly, mice deficient in both MGP and OPN had twice as much arterial calcification as MGP−/− OPN+/+ at 2 wk, and over 3 times as much at 4 wk, suggesting an inhibitory effect of OPN in vascular calcification. Moreover, these mice died significantly earlier (4.4 ± 0.2 wk) than MGP−/− OPN+/+ counterparts (6.6 ± 1.0 wk). The cause of death in these animals was found to be vascular rupture followed by hemorrhage, most likely due to enhanced calcification. These studies are the first to demonstrate a role for OPN as an inducible inhibitor of ectopic calcification in vivo.

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The Inhibitory Roles of Vitamin K in Progression of Vascular Calcification

Nutrients ◽

10.3390/nu12020583 ◽

2020 ◽

Vol 12 (2) ◽

pp. 583 ◽

Cited By ~ 3

Author(s):

Atsushi Shioi ◽

Tomoaki Morioka ◽

Tetsuo Shoji ◽

Masanori Emoto

Keyword(s):

Vascular Calcification ◽

Vitamin K ◽

Osteoblastic Differentiation ◽

Oncostatin M ◽

Matrix Gla Protein ◽

In Vivo Studies ◽

Arterial Calcification ◽

Anti Inflammatory

Vitamin K is a fat-soluble vitamin that is indispensable for the activation of vitamin K-dependent proteins (VKDPs) and may be implicated in cardiovascular disease (CVD). Vascular calcification is intimately associated with CV events and mortality and is a chronic inflammatory process in which activated macrophages promote osteoblastic differentiation of vascular smooth muscle cells (VSMCs) through the production of proinflammatory cytokines such as IL-1β, IL-6, TNF-α, and oncostatin M (OSM) in both intimal and medial layers of arterial walls. This process may be mainly mediated through NF-κB signaling pathway. Vitamin K has been demonstrated to exert anti-inflammatory effects through antagonizing NF-κB signaling in both in vitro and in vivo studies, suggesting that vitamin K may prevent vascular calcification via anti-inflammatory mechanisms. Matrix Gla protein (MGP) is a major inhibitor of soft tissue calcification and contributes to preventing both intimal and medial vascular calcification. Vitamin K may also inhibit progression of vascular calcification by enhancing the activity of MGP through facilitating its γ-carboxylation. In support of this hypothesis, the procalcific effects of warfarin, an antagonist of vitamin K, on arterial calcification have been demonstrated in several clinical studies. Among the inactive MGP forms, dephospho-uncarboxylated MGP (dp-ucMGP) may be regarded as the most useful biomarker of not only vitamin K deficiency, but also vascular calcification and CVD. There have been several studies showing the association of circulating levels of dp-ucMGP with vitamin K intake, vascular calcification, mortality, and CVD. However, additional larger prospective studies including randomized controlled trials are necessary to confirm the beneficial effects of vitamin K supplementation on CV health.

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MGP T-138C Polymorphism (TT Genotype) is Associated with Vascular Calcification Incidence in Indonesian Regular Hemodialysis Patients

The Indonesian Biomedical Journal ◽

10.18585/inabj.v12i4.1162 ◽

2020 ◽

Vol 12 (4) ◽

pp. 320-324

Author(s):

Muhammad Hanif Wibowo ◽

Riri Andri Muzasti ◽

Syafrizal Nasution

Keyword(s):

Vascular Calcification ◽

Matrix Gla Protein ◽

P Value ◽

Mineral Deposition ◽

Pcr Rflp ◽

Common Causes ◽

The Matrix ◽

Polymerase Chain ◽

Control Study ◽

Regular Hemodialysis

BACKGROUND: Vascular calcification contributes greatly to the incidence of cardiovascular disease. Previously, vascular calcification was considered as a passive process caused by the mineral deposition from the circulation. Nowadays, researchers have found inhibitors and promoter factors from vascular calcification, one of which is the matrix gla protein (MGP). MGP levels depend on the gene that encodes them. The MGP T-138C polymorphism is one of the most common causes of vascular calcification.METHODS: This was a case-control study involving 86 chronic kidney disease (CKD) patients who underwent regular hemodialysis in Rasyida Kidney Hospital, Medan, Indonesia. Vascular calcification was determined from lateral and posteroanterior abdominal X-ray. The MGP T-138 C polymorphism was analyzed using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP).RESULTS: The TT/TC genotype associates with the incidence of vascular calcification with OR of 3.52, 95% CI: 1.23-10.106 (p-value<0.001).CONCLUSION: There is an association between MGP T-138C polymorphism, particularly on T Allele with the incidence of vascular calcification in CKD patients undergoing regular hemodialysis.KEYWORDS: hemodialysis, T-138 C polymorphism, vascular calcification, matrix GLA protein

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The relationship between the Spine Deformity Index, biochemical parameters of bone metabolism and vascular calcifications: results from the Epidemiological VERtebral FRACtures iTalian Study (EVERFRACT) in dialysis patients

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2014-0194 ◽

2014 ◽

Vol 0 (0) ◽

Cited By ~ 2

Author(s):

Maria Fusaro ◽

Maurizio Gallieni ◽

Marianna Noale ◽

Giovanni Tripepi ◽

Davide Miozzo ◽

...

Keyword(s):

Bone Metabolism ◽

Vertebral Fractures ◽

Ldl Cholesterol ◽

Matrix Gla Protein ◽

Arterial Calcification ◽

Spine Deformity ◽

Vascular Calcifications ◽

Bone Metabolism Markers ◽

Spine Deformity Index ◽

The Relationship

AbstractThe Spine Deformity Index (SDI) is a measure of vertebral fractures (VFs), providing information on both their number and severity.We evaluated the relationships between SDI and clinical, biochemical and arterial calcification parameters in 387 hemodialysis (HD) patients. VFs, assessed by quantitative vertebral morphometry, and vascular calcifications were identified in the same lateral spinal X-ray. To improve the detection of fracture severity, we created a corrected SDI (c-SDI), by dividing SDI for the number of VFs. We assessed routine biochemistry, bone-Gla-protein (BGP), undercaboxylated BGP (ucBGP), and matrix-Gla-protein (MGP).VFs prevalence was 55.3%. HD patients with a SDI >1 were more frequently males (p<0.05), and had lower BGP (p<0.01). Patients with a c-SDI >1 had higher LDL-cholesterol (p<0.05) and lower ucBGP (p<0.05) and MGP (p<0.05). Calcifications of the abdominal aorta (AAoC) were more frequent in patients with SDI >1 (p<0.05) and with c-SDI >1 (p<0.05). Multivariate logistic regression showed that male sex (OR 1.86, CI 1.20–2.91), age (OR 1.03, CI 1.01–1.05) and albumin ≥3.5 g/dL (OR 0.54, CI 0.31–0.93) were predictors of a SDI >1. Age (OR 1.05, CI 1.03–1.07), LDL-cholesterol (OR 1.74, CI 1.04–2.92) and ucBGP (OR 0.35, CI 0.18–0.70) were associated with c-SDI >1.We conclude that the severity of VFs was associated with age, atherogenic factors and bone metabolism markers.

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Chronic coumarin treatment is associated with increased extracoronary arterial calcification in humans

Blood ◽

10.1182/blood-2010-01-264598 ◽

2010 ◽

Vol 115 (24) ◽

pp. 5121-5123 ◽

Cited By ~ 72

Author(s):

Roger J. M. W. Rennenberg ◽

Bernard J. van Varik ◽

Leon J. Schurgers ◽

Karly Hamulyak ◽

Hugo ten Cate ◽

...

Keyword(s):

Risk Factors ◽

Cardiovascular Risk ◽

Vascular Calcification ◽

Vitamin K ◽

Vitamin K Antagonists ◽

Cross Sectional Study ◽

Matrix Gla Protein ◽

Arterial Calcification ◽

Cross Sectional

Abstract Vascular calcification is a marker of increased cardiovascular risk. Vitamin K–dependent matrix Gla protein (MGP) is important in inhibiting calcification. Because MGP activation is vitamin K dependent, we performed a cross-sectional study investigating the relationship between the use of vitamin K antagonists and extracoronary vascular calcification. From the Dutch thrombosis services we selected 19 patients younger than 55 years who had no other cardiovascular risk factors and who had used coumarins for more than 10 years, and compared these to 18 matched healthy controls. MGP was measured, and a plain x-ray of the thighs was taken to assess femoral arterial calcifications. The odds ratio for calcification in patients versus controls was 8.5 (95% confidence interval [CI] 2.01-35.95). Coumarin use and MGP were associated with calcification, even after adjusting for other risk factors. We conclude that long-term use of coumarins is associated with enhanced extracoronary vascular calcification, possibly through the inhibition of MGP carboxylation.

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