Matrix Gla Protein Abstracts 1

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High Dephosphorylated-Uncarboxylated MGP in Hemodialysis patients: risk factors and response to vitamin K
            (Aoun et al., 2017)  Download
BACKGROUND:  Vascular calcifications are highly prevalent in hemodialysis patients. Dephosphorylated-uncarboxylated MGP (dp-ucMGP) was found to increase in vitamin K-deficient patients and may be associated with vascular calcifications. Supplementation of hemodialysis patients with vitamin K METHODS:  This is a prospective, pre-post intervention clinical trial involving 50 hemodialysis patients who received daily 360 μg of menaquinone-7 for 4 weeks. At baseline they were assessed for plasma dp-ucMGP levels and vascular calcification scores (AC-24) as well as for other demographic, clinical and biological variables. Dp-ucMGP levels were measured a second time at 4 weeks. RESULTS:  At baseline, dp-ucMGP levels were extremely elevated with a median of 3179.15 (1825.25; 4339.50) pM and correlated significantly with AC-24 (Spearman's rho = 0.43, P = 0.002). Using a bivariate regression analysis, the association between dp-ucMGP levels and AC-24 was most significant when comparing dp-ucMGP levels less than 1000 to those more than 1000 pM (P = 0.02). Dp-ucMGP levels higher than 5000 pM were significantly associated with females, patients with recent fracture and patients with lower serum albumin (respectively P = 0.02, 0.004 and 0.046). The average drop of dp-ucMGP at 4 weeks of treatment was found to be 86% with diabetics having the lowest drop rate (P = 0.01). CONCLUSION:  Vitamin K deficiency, as assessed by high dp-ucMGP levels, is profound in hemodialysis patients from the Eastern Mediterranean region and it is significantly correlated with vascular calcifications. Daily 360 μg of menaquinone-7, given for 4 weeks, effectively reduces dp-ucMGP in this population. Future studies are needed to assess the changes in vascular calcifications in hemodialysis patients treated with vitamin K TRIAL REGISTRATION:  The clinical trial was registered on clinicaltrials.gov (Identification number NCT02876354 , on August 11, 2016).


 

Beneficial effects of vitamins D and K on the elastic properties of the vessel wall in postmenopausal women: a follow-up study.
            (Braam et al., 2004)  Download
Matrix-Gla Protein (MGP) is a strong inhibitor of vascular calcification, the expression of which is vitamin D dependent. MGP contains five gamma-carboxyglutamic acid (Gla)-residues which are formed in a vitamin K-dependent carboxylation step and which are essential for its function. Hence vascular vitamin K-deficiency will result in undercarboxylated, inactive MGP which is a potential risk factor for calcification. In the present study we describe the effects of vitamin K1 and D supplementation on vascular properties in postmenopausal women. In a randomized placebo-controlled intervention study, 181 postmenopausal women were given either a placebo or a supplement containing minerals and vitamin D (MD-group), or the same supplement with vitamin K1 (MDK-group). 150 participants completed the study and analysis was performed on 108 participants. At baseline and after three years, vessel wall characteristics, including compliance coefficient (CC), distensibility coefficient (DC), intima-media thickness (IMT) and the Young's Modulus (E) were measured to assess the effect of the supplements on the change of these parameters. The results showed that the elastic properties of the common carotid artery in the MDK-group remained unchanged over the three-year period, but decreased in the MD- and placebo-group. Comparing the MDK- and placebo-group, there were significant differences in decrease of DC (8.8%; p<0.05), CC (8.6%; p<0.05), and in increase of PP (6.3%; p<0.05) and E (13.2%, p<0.01). There were no significant differences between the MD-group and placebo. No significant differences were observed in the change of IMT between the three groups. It is concluded that a supplement containing vitamins K1 and D has a beneficial effect on the elastic properties of the arterial vessel wall.

Matrix-Gla protein and vascular calcification: the negative role of oral anticoagulant therapy.
            (Cozzolino, 2009)  Download
With great interest I read the article by Koos et al. (1) on the association between low circulating inactive Matrix-Gla Protein (ucMGP) levels and the degree of calcification in patients with aortic valve disease published in this issue of Thrombosis and Haemostasis. The authors’ results support one of the potential mechanisms involved in vascular calcification (VC): the treatment with oral anticoagulant inhibits MGP activation and local expression by impairing vitamin K production. I found the manuscript to be of real interest, and I would like to discuss why these results may be important for the clinical point of view, in particular for chronic kidney disease (CKD) patients.


 

The circulating inactive form of matrix Gla Protein (ucMGP) as a biomarker for cardiovascular calcification.
            (Cranenburg et al., 2008)  Download
OBJECTIVE:  Matrix gamma-carboxyglutamate (Gla) protein (MGP) is a vitamin K-dependent protein and a strong inhibitor of vascular calcification. Vitamin K deficiency leads to inactive uncarboxylated MGP (ucMGP), which accumulates at sites of arterial calcification. We hypothesized that as a result of ucMGP deposition around arterial calcification, the circulating fraction of ucMGP is decreased. Here we report on the development of an ucMGP assay and the potential diagnostic utility of monitoring serum ucMGP levels. METHODS AND RESULTS:  An ELISA-based assay was developed with which circulating ucMGP can be determined. Serum ucMGP levels were measured in healthy subjects (n = 165) and in four patient populations; patients who underwent angioplasty (n = 30), patients with aortic stenosis (n = 25), hemodialysis patients (n = 52), and calciphylaxis patients (n = 10). All four patient populations had significantly lower ucMGP levels. In angioplasty patients and in those with aortic stenosis, some overlap was observed with the control population. However, in the hemodialysis and calciphylaxis populations, virtually all subjects had ucMGP levels below the normal adult range. CONCLUSION:  Serum ucMGP may be used as a biomarker to identify those at risk for developing vascular calcification. This assay may become an important tool in the diagnosis of cardiovascular calcification.

Uncarboxylated matrix Gla protein (ucMGP) is associated with coronary artery calcification in haemodialysis patients.
            (Cranenburg et al., 2009)  Download
Matrix gamma-carboxyglutamate (Gla) protein (MGP) is a potent local inhibitor of cardiovascular calcification and accumulates at areas of calcification in its uncarboxylated form (ucMGP). We previously found significantly lower circulating ucMGP levels in patients with a high vascular calcification burden. Here we report on the potential of circulating ucMGP to serve as a biomarker for vascular calcification in haemodialysis (HD) patients. Circulating ucMGP levels were measured with an ELISA-based assay in 40 HD patients who underwent multi-slice computed tomography (MSCT) scanning to quantify the extent of coronary artery calcification (CAC). The mean ucMGP level in HD patients (193 +/- 65 nM) was significantly lower as compared to apparently healthy subjects of the same age (441 +/- 97 nM; p < 0.001) and patients with rheumatoid arthritis (RA) without CAC (560 +/- 140 nM; p < 0.001). Additionally, ucMGP levels correlated inversely with CAC scores (r = -0.41; p = 0.009), and this correlation persisted after adjustment for age, dialysis vintage and high-sensitivity C-reactive protein (hs-CRP). Since circulating ucMGP levels are significantly and inversely correlated with the extent of CAC in HD patients, ucMGP may become a tool for identifying HD patients with a high probability of cardiovascular calcification.

The effect of menaquinone-7 supplementation on circulating species of matrix Gla protein.
            (Dalmeijer et al., 2012)  Download
OBJECTIVE:  To investigate whether menaquinone-7 (MK-7) supplementation increases carboxylation of MGP. DESIGN:  A randomized, double-blind, placebo-controlled trial was performed. Sixty participants (40-65 y) were randomly allocated to supplementation of 180 μg/d, 360 μg/d of MK-7 or placebo during 12 weeks. At baseline, after 4 and 12 weeks, desphospho-uncarboxylated MGP (dp-ucMGP), desphospho-carboxylated MGP (dp-cMGP) and total uncarboxylated MGP (t-ucMGP) were measured by ELISA techniques. Furthermore, the ratio of uncarboxylated osteocalcin (ucOC) to carboxylated osteocalcin (cOC) was used as proxy of vitamin K status and various cardiovascular risk factors were measured. RESULTS:  Dp-ucMGP decreased significantly and dose-dependently in the 180 μg and 360 μg MK-7 supplementation groups (P time*treatment < 0.001) after 12 weeks, by 31% and 46% respectively, while dp-ucMGP levels remained unchanged after placebo treatment. The osteocalcin ratio also decreased significantly after 12-week supplementation with 180 μg (60%) and 360 μg (74%) MK-7 (P time*treatment < 0.001), while levels remained unchanged after placebo treatment. These results indicate improved vitamin K status and good compliance to the study treatment. Changes over time of dp-cMGP (p = 0.42) and t-ucMGP (p = 0.23) levels did not differ between treatment arms. Other cardiovascular risk factors did not differ between treatments arms. CONCLUSIONS:  Menaquinone supplementation dose-dependently decreases dp-ucMGP concentrations, but does not affect other MGP species. Dp-ucMGP may serve as a non-invasive marker of vitamin K status.

Prophylactic role of vitamin K supplementation on vascular inflammation in type 2 diabetes by regulating the NF-κB/Nrf2 pathway via activating Gla proteins.
            (Dihingia et al., 2018)  Download
There is no previous study that has examined the relationship between circulating vitamin K1 (VK1) and vascular inflammation in type 2 diabetes (T2D). This study aims to examine the hypothesis that circulating VK1 deficiency may be associated with higher inflammation and insulin resistance in T2D patients and that VK1 supplementation regulates the NF-κB/Nrf2 pathway via activating VK-dependent Gla proteins and reduces vascular inflammation. The results showed that plasma VK1 levels were significantly lower and MCP-1, fasting glucose, HbA1c, and insulin resistance (HOMA-IR) were significantly higher in T2D patients compared to those in the controls. The lower levels of VK1 in T2D patients were significantly and inversely correlated with MCP-1 and HOMA-IR, which suggests that VK1 supplementation may reduce the vascular inflammation and insulin resistance in T2D. Using a high fat diet-fed T2D mice model this study further demonstrated that VK1 supplementation (1, 3, 5 μg per kg BW, 8 weeks) dose-dependently decreased the body weight gain, glucose intolerance, fasting glucose, glycated hemoglobin, HOMA-IR, and cytokine secretion (MCP-1 and IL-6) in T2D mice. Further cell culture studies showed that VK1 supplementation (1, 5, or 10 nM) decreased NF-κB phosphorylation and MCP-1 secretion and increased Nrf2 protein expression in high glucose (HG, 25 mM)-treated monocytes. Signal silencing studies with GGCX siRNA again depicted the role of VK-dependent Gla proteins in mediating the effect of VK1 on vascular inflammation in HG-treated cells. In conclusion, this study suggests that circulating VK1 has a positive effect in lowering vascular inflammation in T2D by regulating NF-κB/Nrf2 transcription factors via activating VK-dependent Gla proteins.

Relation of circulating Matrix Gla-Protein and anticoagulation status in patients with aortic valve calcification.
            (Koos et al., 2009)  Download
Matrix-Gla Protein (MGP) is a vitamin K-dependent protein acting as a local inhibitor of vascular calcification. Vitamin K-antagonists (oral anticoagulant; OAC) inhibit the activation of MGP by blocking vitamin K-metabolism. The aim of this study was to investigate the effect of long-term OAC treatment on circulating MGP levels in humans and on MGP expression in mice. Additionally, we tested the association between circulating inactive MGP (ucMGP) levels and the presence and severity of AVC in patients with aortic valve disease (AVD). We analysed circulating ucMGP levels in 191 consecutive patients with echocardiographically proven calcific AVD and 35 control subjects. The extent of AVC in the patients was assessed by multislice spiral computed tomography. Circulating ucMGP levels were significantly lower in patients with AVD (348.6 +/- 123.1 nM) compared to the control group (571.6 +/- 153.9 nM, p < 0.001). Testing the effect of coumarin in mice revealed that also the mRNA expression of MGP in the aorta was downregulated. Multifactorial analysis revealed a significant effect of glomerular filtration rate and long-term OAC therapy on circulating ucMGP levels in the patient group. Subsequently, patients on long-term OAC had significantly increased AVC scores. In conclusion, patients with calcific AVD had significantly lower levels of circulating ucMGP as compared to a reference population, free of coronary and valvular calcifications. In addition, our data suggest that OAC treatment may decrease local expression of MGP, resulting in decreased circulating MGP levels and subsequently increased aortic valve calcifications as an adverse side effect.


 

Vitamin K2 supplementation and arterial stiffness among renal transplant recipients-a single-arm, single-center clinical trial.
            (Mansour et al., 2017)  Download
Subclinical vitamin K deficiency is prevalent among renal transplant recipients and is associated with an increased risk of cardiovascular disease. However, the association between vitamin K supplementation and improvement of arterial stiffness has not been explored in the renal transplant population. The KING trial (vitamin K2 In reNal Graft) is a single-arm study that evaluated the association between the change in vitamin K status and indices of arterial stiffness following 8 weeks of menaquinone-7 (vitamin K2) supplementation (360 μg once daily) among renal transplant recipients (n = 60). Arterial stiffness was measured using carotid-femoral pulse wave velocity (cfPWV). Subclinical vitamin K deficiency was defined as plasma concentration of dephosphorylated-uncarboxylated matrix Gla protein (dp-ucMGP) >500 pmol/L.At baseline, 53.3% of the study subjects had subclinical vitamin K deficiency. Supplementation was associated with a 14.2% reduction in mean cfPWV at 8 weeks (cfPWV pre-vitamin K2 = 9.8 ± 2.2 m/s vs. cfPWV post-vitamin K2 = 8.4 ± 1.5 m/s; P < .001). Mean dp-ucMGP concentrations were also significantly reduced by 55.1% following menaquinone-7 supplementation with a reduction in the prevalence of subclinical deficiency by 40% (P = .001). When controlled for age, durations of hemodialysis and transplantation, and the change in 24-hour mean arterial pressure, the improvement in arterial stiffness was independently associated with the reduction in dp-ucMGP concentration (P = .014).Among renal transplant recipients with stable graft function, vitamin K2 supplementation was associated with improvement in subclinical vitamin K deficiency and arterial stiffness. (Clinicaltrials.gov: NCT02517580).

Matrix Gla protein polymorphism, but not concentrations, is associated with radiographic hand osteoarthritis.
            (Misra et al., 2011)  Download
OBJECTIVE:  Factors associated with mineralization and osteophyte formation in osteoarthritis (OA) are incompletely understood. Genetic polymorphisms of matrix Gla protein (MGP), a mineralization inhibitor, have been associated clinically with conditions of abnormal calcification. We therefore evaluated the relationship of MGP concentrations and polymorphisms at the MGP locus to hand OA. METHODS:  Ours was an ancillary study to a 3-year randomized trial assessing the effect of vitamin K supplementation on vascular calcification and bone loss among community-dwelling elders. We studied participants who had serum MGP concentration measured and DNA genotyped for 3 MGP genetic polymorphisms (rs1800802, rs1800801, and rs4236), and who had hand radiographs. We evaluated the cross-sectional associations of serum MGP and the 3 MGP genetic polymorphisms, respectively, with radiographic hand OA using logistic regression with generalized estimating equations, adjusting for potential confounders. RESULTS:  Radiographic hand OA in ≥ 1 joint was present in 71% of the 376 participants (mean age 74 years, mean body mass index 28 kg/m(2), 59% women). No significant association between serum MGP concentrations and radiographic hand OA was found [adjusted OR 1.0 (ref), 1.40, 1.21, and 1.21 for quartiles 1-4, respectively]. Homozygosity of the rs1800802 minor allele was associated with 0.56 times lower prevalence of hand OA compared with having ≥ 1 major allele at this locus (95% CI 0.32-0.99, p = 0.046). CONCLUSION:  There may be an association between hand OA and genetic polymorphism at the MGP locus that is not reflected by total MGP serum concentrations. Further studies are warranted to replicate and elucidate potential mechanisms underlying these observed associations.

Association of kidney function and uncarboxylated matrix Gla protein: data from the Heart and Soul Study.
            (Parker et al., 2009)  Download
BACKGROUND:  Vascular calcification is highly prevalent in persons with chronic kidney disease (CKD) and predicts cardiovascular disease (CVD) events. Matrix Gla protein (MGP) is a potent inhibitor of vascular calcification, and lower levels of its precursor-uncarboxylated MGP (ucMGP)--are associated with vascular calcification and atherosclerosis. Whether mild to moderate decrements in kidney function are associated with lower serum ucMGP is unknown. METHODS:  In a cross-sectional study among 842 outpatients with stable CVD, estimated glomerular filtration rate (eGFR), serum cystatin-C and urine albumin-to-creatinine ratio (ACR) were measured and serum ucMGP levels were determined by ELISA. Multivariate linear regression evaluated the association of each kidney function measure with serum ucMGP levels. RESULTS:  The mean eGFR was 76 +/- 23 mL/min/1.73 m(2), and 186 subjects (22%) had moderate CKD (eGFR <60 mL/min/1.73 m(2)). The mean +/- SD ucMGP level was 3289 +/- 1177 nM. In unadjusted analysis, each 10 mL/ min/1.73 m(2) lower eGFR was associated with 101 nM lower ucMGP level. This association was only minimally attenuated in final multivariate models wherein each 10 mL/ min/1.73 m(2) lower eGFR was associated with 79 nM lower ucMGP (95% confidence interval [CI]; 44 to 115; P < 0.001) after adjustment for age, sex, race, body mass index, blood pressure, smoking, hypertension, diabetes; and serum albumin, calcium, phosphorus, and fetuin-A levels. Similarly, in models adjusted for identical covariates, each 0.1 mg/L higher cystatin-C was associated with 39 nM lower ucMGP (95% CI 23 to 55; P < 0.001). In contrast, no significant association was observed between ACR and ucMGP in either unadjusted or adjusted analyses (adjusted P = 0.17). All associations were similar among subjects with or without diabetes (P-values for interaction > 0.50). CONCLUSIONS:  Among outpatients with stable CVD, a reduced glomerular filtration rate is associated with a decreased serum ucMGP level. In contrast, ACR is not associated with ucMGP levels. Whether ucMGP is a useful marker of vascular calcification and CVD event risk in persons with CKD deserves future study.


Matrix Gla-protein: the calcification inhibitor in need of vitamin K.
            (Schurgers et al., 2008)  Download
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.

Vitamin K supplementation and progression of coronary artery calcium in older men and women.
            (Shea et al., 2009)  Download
BACKGROUND:  Coronary artery calcification (CAC) is an independent predictor of cardiovascular disease. A preventive role for vitamin K in CAC progression has been proposed on the basis of the properties of matrix Gla protein (MGP) as a vitamin K-dependent calcification inhibitor. OBJECTIVE:  The objective was to determine the effect of phylloquinone (vitamin K1) supplementation on CAC progression in older men and women. DESIGN:  CAC was measured at baseline and after 3 y of follow-up in 388 healthy men and postmenopausal women; 200 received a multivitamin with 500 microg phylloquinone/d (treatment), and 188 received a multivitamin alone (control). RESULTS:  In an intention-to-treat analysis, there was no difference in CAC progression between the phylloquinone group and the control group; the mean (+/-SEM) changes in Agatston scores were 27 +/- 6 and 37 +/- 7, respectively. In a subgroup analysis of participants who were > or =85% adherent to supplementation (n = 367), there was less CAC progression in the phylloquinone group than in the control group (P = 0.03). Of those with preexisting CAC (Agatston score > 10), those who received phylloquinone supplements had 6% less progression than did those who received the multivitamin alone (P = 0.04). Phylloquinone-associated decreases in CAC progression were independent of changes in serum MGP. MGP carboxylation status was not determined. CONCLUSIONS:  Phylloquinone supplementation slows the progression of CAC in healthy older adults with preexisting CAC, independent of its effect on total MGP concentrations. Because our data are hypothesis-generating, further studies are warranted to clarify this mechanism. This trial was registered at clinicaltrials.gov as NCT00183001.

Effects of citicoline on level of consciousness, serum level of fetuin-A and matrix Gla-protein (MGP) in trauma patients with diffuse axonal injury (DAI) and GCS≤8.
            (Shokouhi et al., 2014)  Download
BACKGROUND:  Citicoline, a neuroprotective drug, has been suggested to improve level of consciousness, mitigating secondary to brain damage and ectopic vascular calcification, following post-traumatic neurogenesis and angiogenesis, inducing calcification modulators, like fetuin-A and matrix Gla-protein (MGP). This study aimed to investigate effects of citicoline on levels of consciousness, serum levels of fetuin-A and MGP in patients with severe traumatic brain injury. METHODS:  This double blind randomized controlled trial (RCT) was conducted on patients with diagnosis of diffuse axonal injury (DAI) and GCS≤8. The cases were treated with citicoline (500 mg every 6 hours) intravenously for fifteen days. Daily GCS assessment and intermittent blood sampling were done for both cases and controls. RESULTS:  Fifty-eight patients were included in the study and during the study period, mean GCS levels improved in both groups; however, the difference was inconsiderable (p>0.05). Serum levels of fetuin-A, a negative phase reactant, increased in the group treated with citicoline (p=0.012), while these changes were insignificant for the controls (p=0.455). Serum levels of MGP, a calcification inhibitor, increased in the cases (p=0.046). The alterations were inconsequential in the control group (p=0.405). CONCLUSION:  The findings of this study suggest neutral effects of citicoline on level of consciousness and GCS. Through increasing levels of fetuin-A and MGP, citicoline may have protective effects against inflammatory damage and vascular calcification secondary to head trauma.

Vitamin K status in healthy volunteers.
            (Theuwissen et al., 2014)  Download
Vitamin K's recommended dietary allowance (RDA) is based on the hepatic requirement for clotting factor synthesis, but substantial concentrations of undercarboxylated extra-hepatic Gla-proteins are found in the circulation of non-supplemented individuals. This suggests that vitamin K intake above the RDA is required for an optimal extra-hepatic vitamin K status. Circulating uncarboxylated osteocalcin (ucOC) and desphospho-uncarboxylated matrix Gla-protein (dp-ucMGP) are considered markers of the vitamin K status in bone and the vasculature, respectively. We measured these markers in 896 samples of healthy volunteers and defined target groups for vitamin K supplementation based on increased levels indicative of tissue-specific vitamin K deficiency. We studied the response to vitamin K supplements at different states of vitamin K deficiency by measuring the circulating dp-ucMGP level in samples from two short-term trials on menaquinone-7 (MK-7, vitamin K2) supplementation in 42 children and 68 adults. Children had high ucOC levels (3.4-96.9 ng ml(-1)); other age groups had values in the range of 1.5-5.0 ng ml(-1). From the age of 40 years, dp-ucMGP levels gradually increased. Children and adults with more pronounced vitamin K deficiency gave the highest responses to MK-7 supplementation. Children and adults above 40 years showed the largest tissue-specific vitamin deficiency and accordingly may benefit from MK-7 supplementation to improve their extra-hepatic vitamin K status.

 


References

Aoun, M, et al. (2017), ‘High Dephosphorylated-Uncarboxylated MGP in Hemodialysis patients: risk factors and response to vitamin K’, BMC Nephrol, 18 (1), 191. PubMed: 28592319
Braam, LA, et al. (2004), ‘Beneficial effects of vitamins D and K on the elastic properties of the vessel wall in postmenopausal women: a follow-up study.’, Thromb Haemost, 91 (2), 373-80. PubMed: 14961167
Cozzolino, M (2009), ‘Matrix-Gla protein and vascular calcification: the negative role of oral anticoagulant therapy.’, Thromb Haemost, 101 (4), 605-6. PubMed: 19350099
Cranenburg, EC, et al. (2008), ‘The circulating inactive form of matrix Gla Protein (ucMGP) as a biomarker for cardiovascular calcification.’, J Vasc Res, 45 (5), 427-36. PubMed: 18401181
Cranenburg, EC, et al. (2009), ‘Uncarboxylated matrix Gla protein (ucMGP) is associated with coronary artery calcification in haemodialysis patients.’, Thromb Haemost, 101 (2), 359-66. PubMed: 19190822
Dalmeijer, GW, et al. (2012), ‘The effect of menaquinone-7 supplementation on circulating species of matrix Gla protein.’, Atherosclerosis, 225 (2), 397-402. PubMed: 23062766
Dihingia, A, et al. (2018), ‘Prophylactic role of vitamin K supplementation on vascular inflammation in type 2 diabetes by regulating the NF-κB/Nrf2 pathway via activating Gla proteins.’, Food Funct, 9 (1), 450-62. PubMed: 29227493
Koos, R, et al. (2009), ‘Relation of circulating Matrix Gla-Protein and anticoagulation status in patients with aortic valve calcification.’, Thromb Haemost, 101 (4), 706-13. PubMed: 19350115
Mansour, AG, et al. (2017), ‘Vitamin K2 supplementation and arterial stiffness among renal transplant recipients-a single-arm, single-center clinical trial.’, J Am Soc Hypertens, 11 (9), 589-97. PubMed: 28756183
Misra, D, et al. (2011), ‘Matrix Gla protein polymorphism, but not concentrations, is associated with radiographic hand osteoarthritis.’, J Rheumatol, 38 (9), 1960-65. PubMed: 21724703
Parker, BD, et al. (2009), ‘Association of kidney function and uncarboxylated matrix Gla protein: data from the Heart and Soul Study.’, Nephrol Dial Transplant, 24 (7), 2095-101. PubMed: 19204017
Schurgers, LJ, EC Cranenburg, and C Vermeer (2008), ‘Matrix Gla-protein: the calcification inhibitor in need of vitamin K.’, Thromb Haemost, 100 (4), 593-603. PubMed: 18841280
Shea, MK, et al. (2009), ‘Vitamin K supplementation and progression of coronary artery calcium in older men and women.’, Am J Clin Nutr, 89 (6), 1799-807. PubMed: 19386744
Shokouhi, G, et al. (2014), ‘Effects of citicoline on level of consciousness, serum level of fetuin-A and matrix Gla-protein (MGP) in trauma patients with diffuse axonal injury (DAI) and GCS≤8.’, Ulus Travma Acil Cerrahi Derg, 20 (6), 410-16. PubMed: 25541919
Theuwissen, E, et al. (2014), ‘Vitamin K status in healthy volunteers.’, Food Funct, 5 (2), 229-34. PubMed: 24296867