Publications by authors named "Cees Vermeer"

129 Publications

Amentadione from the Alga as a Novel Osteoarthritis Protective Agent in an Ex Vivo Co-Culture OA Model.

Mar Drugs 2020 Dec 7;18(12). Epub 2020 Dec 7.

Centre of Marine Sciences (CCMAR), University of Algarve, 8005-139 Faro, Portugal.

Osteoarthritis (OA) remains a prevalent chronic disease without effective prevention and treatment. Amentadione (YP), a meroditerpenoid purified from the alga , has demonstrated anti-inflammatory activity. Here, we investigated the YP anti-osteoarthritic potential, by using a novel OA preclinical drug development pipeline designed to evaluate the anti-inflammatory and anti-mineralizing activities of potential OA-protective compounds. The workflow was based on in vitro primary cell cultures followed by human cartilage explants assays and a new OA co-culture model, combining cartilage explants with synoviocytes under interleukin-1β (IL-1β) or hydroxyapatite (HAP) stimulation. A combination of gene expression analysis and measurement of inflammatory mediators showed that the proposed model mimicked early disease stages, while YP counteracted inflammatory responses by downregulation of COX-2 and IL-6, improved cartilage homeostasis by downregulation of MMP3 and the chondrocytes hypertrophic differentiation factors Col10 and Runx2. Importantly, YP downregulated NF-κB gene expression and decreased phosphorylated IkBα/total IkBα ratio in chondrocytes. These results indicate the co-culture as a relevant pre-clinical OA model, and strongly suggest YP as a cartilage protective factor by inhibiting inflammatory, mineralizing, catabolic and differentiation processes during OA development, through inhibition of NF-κB signaling pathways, with high therapeutic potential.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/md18120624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762386PMC
December 2020

The coincidence of low vitamin K status and high expression of growth differentiation factor 15 may indicate increased mortality risk in stable coronary heart disease patients.

Nutr Metab Cardiovasc Dis 2021 02 22;31(2):540-551. Epub 2020 Sep 22.

Cardiovascular Research Institute CARIM, Maastricht University, the Netherlands.

Background And Aims: Matrix Gla protein (MGP) is a natural inhibitor of vascular calcification critically dependent on circulating vitamin K status. Growth differentiation factor 15 (GDF-15) is a regulatory cytokine mainly of the inflammatory and angiogenesis pathways, but potentially also involved in bone mineralization. We sought to determine whether these two circulating biomarkers jointly influenced morbidity and mortality risk in patients with chronic coronary heart disease (CHD).

Methods And Results: 894 patients ≥6 months after myocardial infarction and/or coronary revascularization at baseline were followed in a prospective study. All-cause and cardiovascular mortality, non-fatal cardiovascular events (myocardial infarction, stroke, any revascularization), and hospitalization for heart failure (HF) were followed as outcomes. Desphospho-uncarboxylated MGP (dp-ucMGP) was used as a biomarker of vitamin K status. Both, increased concentrations of dp-ucMGP (≥884 pmol/L) and GDF-15 (≥1339 pg/mL) were identified as independent predictors of 5-year all-cause or cardiovascular mortality. However, their coincidence further increased mortality risk. The highest risk was observed in patients with high dp-ucMGP plus high GDF-15, not only when compared with those with "normal" concentrations of both biomarkers [HR 5.51 (95% CI 2.91-10.44), p < 0.0001 and 6.79 (95% CI 3.06-15.08), p < 0.0001 for all-cause and cardiovascular mortality, respectively], but even when compared with patients with only one factor increased. This pattern was less convincing with non-fatal cardiovascular events or hospitalization for HF.

Conclusions: The individual coincidence of low vitamin K status (high dp-ucMGP) and high GDF-15 expression predicts poor survival of stable CHD patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.numecd.2020.09.015DOI Listing
February 2021

Vitamin K metabolism as the potential missing link between lung damage and thromboembolism in Coronavirus disease 2019.

Br J Nutr 2020 Oct 7:1-8. Epub 2020 Oct 7.

Department of Internal Medicine, Canisius-Wilhelmina Hospital, 6532 SZNijmegen, The Netherlands.

Coronavirus disease 2019 (Covid-19), caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2, exerts far-reaching effects on public health and socio-economic welfare. The majority of infected individuals have mild to moderate symptoms, but a significant proportion develops respiratory failure due to pneumonia. Thrombosis is another frequent manifestation of Covid-19 that contributes to poor outcomes. Vitamin K plays a crucial role in the activation of both pro- and anticlotting factors in the liver and the activation of extrahepatically synthesised protein S which seems to be important in local thrombosis prevention. However, the role of vitamin K extends beyond coagulation. Matrix Gla protein (MGP) is a vitamin K-dependent inhibitor of soft tissue calcification and elastic fibre degradation. Severe extrahepatic vitamin K insufficiency was recently demonstrated in Covid-19 patients, with high inactive MGP levels correlating with elastic fibre degradation rates. This suggests that insufficient vitamin K-dependent MGP activation leaves elastic fibres unprotected against SARS-CoV-2-induced proteolysis. In contrast to MGP, Covid-19 patients have normal levels of activated factor II, in line with previous observations that vitamin K is preferentially transported to the liver for activation of procoagulant factors. We therefore expect that vitamin K-dependent endothelial protein S activation is also compromised, which would be compatible with enhanced thrombogenicity. Taking these data together, we propose a mechanism of pneumonia-induced vitamin K depletion, leading to a decrease in activated MGP and protein S, aggravating pulmonary damage and coagulopathy, respectively. Intervention trials should be conducted to assess whether vitamin K administration plays a role in the prevention and treatment of severe Covid-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/S0007114520003979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578635PMC
October 2020

Circulating Receptor Activator of Nuclear Factor kB Ligand and triglycerides are associated with progression of lower limb arterial calcification in type 2 diabetes: a prospective, observational cohort study.

Cardiovasc Diabetol 2020 09 18;19(1):140. Epub 2020 Sep 18.

Sorbonne Université, Paris, France.

Background: Lower limb arterial calcification is a frequent, underestimated but serious complication of diabetes. The DIACART study is a prospective cohort study designed to evaluate the determinants of the progression of lower limb arterial calcification in 198 patients with type 2 diabetes.

Methods: Lower limb arterial calcification scores were determined by computed tomography at baseline and after a mean follow up of 31.20 ± 3.86 months. Serum RANKL (Receptor Activator of Nuclear factor kB Ligand) and bone remodeling, inflammatory and metabolic parameters were measured at baseline. The predictive effect of these markers on calcification progression was analyzed by a multivariate linear regression model.

Results: At baseline, mean ± SD and median lower limb arterial calcification scores were, 2364 ± 5613 and 527 respectively and at the end of the study, 3739 ± 6886 and 1355 respectively. Using multivariate analysis, the progression of lower limb arterial log calcification score was found to be associated with (β coefficient [slope], 95% CI, p-value) baseline log(calcification score) (1.02, 1.00-1.04, p < 0.001), triglycerides (0.11, 0.03-0.20, p = 0.007), log(RANKL) (0.07, 0.02-0.11, p = 0.016), previous ischemic cardiomyopathy (0.36, 0.15-0.57, p = 0.001), statin use (0.39, 0.06-0.72, p = 0.023) and duration of follow up (0.04, 0.01-0.06, p = 0.004).

Conclusion: In patients with type 2 diabetes, lower limb arterial calcification is frequent and can progress rapidly. Circulating RANKL and triglycerides are independently associated with this progression. These results open new therapeutic perspectives in peripheral diabetic calcifying arteriopathy. Trial registration NCT02431234.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12933-020-01122-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501627PMC
September 2020

Reduced vitamin K status as a potentially modifiable risk factor of severe COVID-19.

Clin Infect Dis 2020 Aug 27. Epub 2020 Aug 27.

Department of Pulmonary Medicine, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands.

Background: Respiratory failure and thromboembolism are frequent in SARS-CoV-2-infected patients. Vitamin K activates both hepatic coagulation factors and extrahepatic endothelial anticoagulant protein S, required for thrombosis prevention. In times of vitamin K insufficiency, hepatic procoagulant factors are preferentially activated over extrahepatic proteins. Vitamin K also activates matrix Gla protein (MGP), which protects against pulmonary and vascular elastic fiber damage. We hypothesized that vitamin K may be implicated in coronavirus disease 2019 (COVID-19), linking pulmonary and thromboembolic disease.

Methods: 135 hospitalized COVID-19 patients were compared with 184 historical controls. Poor outcome was defined as invasive ventilation and/or death. Inactive vitamin K-dependent MGP (dp-ucMGP) and prothrombin (PIVKA-II) were measured, inversely related to extrahepatic and hepatic vitamin K status, respectively. Desmosine was measured to quantify the rate of elastic fiber degradation. Arterial calcification severity was assessed by computed tomography.

Results: Dp-ucMGP was elevated in COVID-19 patients compared to controls (p<0.001), with even higher dp-ucMGP in patients with poor outcomes (p<0.001). PIVKA-II was normal in 82.1% of patients. Dp-ucMGP was correlated with desmosine (p<0.001), and coronary artery (p=0.002) and thoracic aortic (p<0.001) calcification scores.

Conclusions: Dp-ucMGP was severely increased in COVID-19 patients, indicating extrahepatic vitamin K insufficiency, which was related to poor outcome while hepatic procoagulant factor II remained unaffected. These data suggest a mechanism of pneumonia-induced extrahepatic vitamin K depletion leading to accelerated elastic fiber damage and thrombosis in severe COVID-19 due to impaired activation of MGP and endothelial protein S, respectively. A clinical trial could assess whether vitamin K administration improves COVID-19 outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciaa1258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499546PMC
August 2020

High expression of Matrix Gla Protein in Schnyder corneal dystrophy patients points to an active role of vitamin K in corneal health.

Acta Ophthalmol 2021 Mar 29;99(2):e171-e177. Epub 2020 Jun 29.

Department of Histology and Embryology, Center of Biostructure Research, Medical University of Warsaw, Warsaw, Poland.

Purpose: Schnyder corneal dystrophy (SCD) is a rare autosomal dominant disorder characterized by corneal lipid accumulation and caused by UBIAD1 pathogenic variants. UBIAD1 encodes a vitamin K (VK) biosynthetic enzyme. To assess the corneal and vascular VK status in SCD patients, we focused on matrix Gla protein (MGP), a VK-dependent protein.

Methods: Conformation-specific immunostainings of different MGP maturation forms were performed on corneal sections and primary keratocytes from corneal buttons of two SCD patients with UBIAD1 p.Asp112Asn and p.Asn102Ser pathogenic variants and unrelated donors. Native or UBIAD1-transfected keratocytes were used for gene expression analysis. Plasma samples from SCD patients (n = 12) and control individuals (n = 117) were subjected for inactive desphospho-uncarboxylated MGP level measurements with an ELISA assay.

Results: Substantial amounts of MGP were identified in human cornea and most of it in its fully matured and active form. The level of mature MGP did not differ between SCD and control corneas. In primary keratocytes from SCD patients, a highly increased MGP expression and presence of immature MGP forms were detected. Significantly elevated plasma concentration of inactive MGP was found in SCD patients.

Conclusion: High amount of MGP and the predominance of mature MGP forms in human cornea indicate that VK metabolism is active in the visual system. Availability of MGP seems of vital importance for a healthy cornea and may be related to protection against corneal calcification. Systemic MGP findings reveal a poor vascular VK status in SCD patients and indicate that SCD may lead to cardiovascular consequences.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/aos.14533DOI Listing
March 2021

Inactive matrix gla protein plasma levels are associated with peripheral neuropathy in Type 2 diabetes.

PLoS One 2020 24;15(2):e0229145. Epub 2020 Feb 24.

Sorbonne Université, Paris, France.

Aims/hypothesis: Diabetic peripheral neuropathy is a frequent and severe complication of diabetes. As Matrix-gla-protein (MGP) is expressed in several components of the nervous system and is involved in some neurological disease, MGP could play a role in peripheral nervous system homeostasis. The aim of this study was to evaluate factors associated with sensitive diabetic neuropathy in Type 2 Diabetes, and, in particular, dephospho-uncarboxylated MGP (dp-ucMGP), the inactive form of MGP.

Methods: 198 patients with Type 2 Diabetes were included. Presence of sensitive diabetic neuropathy was defined by a neuropathy disability score (NDS) ≥6. Plasma levels of dp-ucMGP were measured by ELISA.

Results: In this cohort, the mean age was 64+/-8.4 years old, and 80% of patients were men. Peripheral neuropathy was present in 15.7% of the patients and was significantly associated (r = 0.51, p<0.0001) with dp-ucMGP levels (β = -0.26, p = 0.045) after integrating effects of height (β = -0.38, p = 0.01), insulin treatment (β = 0.42, p = 0.002), retinopathy treated by laser (β = 0.26, p = 0.02), and total cholesterol levels (β = 0.3, p = 0.03) by multivariable analysis.

Conclusions: The association between diabetic neuropathy and the inactive form of MGP suggests the existence of new pathophysiological pathways to explore. Further studies are needed to determine if dp-ucMGP may be used as a biomarker of sensitive neuropathy. Since dp-ucMGP is a marker of poor vitamin K status, clinical studies are warranted to explore the potential protective effect of high vitamin K intake on diabetic peripheral neuropathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229145PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039520PMC
June 2020

Warfarin-induced vitamin K deficiency affects spermatogenesis in Sprague-Dawley rats.

Andrologia 2019 Nov 1;51(10):e13416. Epub 2019 Oct 1.

Department of Anatomic & Molecular Pathology, College of Medicine, University of Lagos, Lagos, Nigeria.

Vitamin K is present in the testes though its actual function in male reproduction is poorly understood. This study investigated the harmful effect of extrahepatic vitamin K insufficiency on the testicular structure. Sprague-Dawley rats were fed with a diet containing warfarin for 2, 4 and 8 weeks; control animals received a standard diet without warfarin. It was found that extrahepatic vitamin K deficiency that is induced by warfarin results in histopathological features that range from delayed spermiation, presence of multinucleated giant cells in the seminiferous tubules, germ cells degeneration, asthenozoospermia, oligozoospermia and increase in the percentage of abnormal sperm morphology when compared to the controls. Data obtained from the two groups were analysed using the Student t test. It is concluded that warfarin-induced vitamin K deficiency has a negative impact on spermatogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/and.13416DOI Listing
November 2019

Renal Resistive Index Is Associated With Inactive Matrix Gla (γ-Carboxyglutamate) Protein in an Adult Population-Based Study.

J Am Heart Assoc 2019 09 12;8(18):e013558. Epub 2019 Sep 12.

Division of Nephrology Geneva University Hospitals Geneva Switzerland.

Background Increased renal resistive index (RRI) has been associated with target organ damage as well as renal and cardiovascular outcomes. Matrix Gla (γ-carboxyglutamate) protein (MGP) is a strong inhibitor of soft tissue calcification. Its inactive form (dephospho-uncarboxylated MGP [dp-ucMGP]) has been associated with vascular stiffness, cardiovascular outcomes, and mortality. In this study, we hypothesized that high levels of dp-ucMGP were associated with increased RRI. Methods and Results We recruited participants via a multicenter family-based cross-sectional study in Switzerland. Levels of dp-ucMGP were measured in plasma by sandwich ELISA. RRI was measured by Doppler ultrasound in 3 segmental arteries in both kidneys. We used mixed regression models to assess the relationship between dp-ucMGP and RRI. We adjusted for common determinants of RRI as well as renal function and cardiovascular risk factors. We included 1006 participants in our analyses: 526 women and 480 men. Mean values were 0.44±0.20 nmol/L for dp-ucMGP and 64±5% for RRI. After multivariable adjustment, dp-ucMGP was positively associated with RRI (=0.001). In subgroup analysis by age tertiles, this association was not significant in the youngest age group (<38 years; =0.62), whereas it was significant in older age groups (38-55 and >55 years; =0.016 and <0.001, respectively). Conclusions Levels of dp-ucMGP are positively and independently associated with RRI after adjustment for common determinants of RRI, cardiovascular risk factors, and renal function. The stronger association among older adults is probably due, in part, to age-related arterial stiffness. RRI thus seems to reflect the global atherosclerotic burden in a general adult population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.119.013558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818003PMC
September 2019

Low Vitamin K Status Is Associated with Increased Elastin Degradation in Chronic Obstructive Pulmonary Disease.

J Clin Med 2019 Jul 27;8(8). Epub 2019 Jul 27.

Department of Pulmonary Medicine, Canisius-Wilhelmina Hospital, 6532 SZ Nijmegen, The Netherlands.

Elastin degradation is accelerated in chronic obstructive pulmonary disease (COPD) and is partially regulated by Matrix Gla Protein (MGP), via a vitamin K-dependent pathway. The aim was to assess vitamin K status in COPD as well as associations between vitamin K status, elastin degradation, lung function parameters and mortality. A total of 192 COPD patients and 186 age-matched controls were included. In addition to this, 290 COPD patients from a second independent longitudinal cohort were also included. Vitamin K status was assessed by measuring plasma inactive MGP levels and rates of elastin degradation by measuring plasma desmosine levels. Reduced vitamin K status was found in COPD patients compared to smoking controls ( < 0.0005) and controls who had never smoked ( = 0.001). Vitamin K status was inversely associated with desmosine (cohort 1: = 0.001; cohort 2: = 0.004). Only few significant associations between vitamin K status and lung function parameters were found. Mortality was higher in COPD patients within the quartile with the lowest vitamin K status compared to those within the other quartiles (hazard ratio 1.85, 95% confidence interval (CI), 1.21-2.83, = 0.005). In conclusion, we demonstrated reduced vitamin K status in COPD and an inverse association between vitamin K status and elastin degradation rate. Our results therefore suggest a potential role of vitamin K in COPD pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm8081116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724066PMC
July 2019

Central Hemodynamics in Relation to Circulating Desphospho-Uncarboxylated Matrix Gla Protein: A Population Study.

J Am Heart Assoc 2019 04;8(7):e011960

1 Studies Coordinating Centre Research Unit Hypertension and Cardiovascular Epidemiology Department of Cardiovascular Sciences University of Leuven Belgium.

Background Stiffening and calcification of the large arteries are forerunners of cardiovascular complications. MGP (Matrix Gla protein), which requires vitamin K-dependent activation, is a potent locally acting inhibitor of arterial calcification. We hypothesized that the central hemodynamic properties might be associated with inactive desphospho-uncarboxylated MGP (dp-uc MGP ). Methods and Results In 835 randomly recruited Flemish individuals (mean age, 49.7 years; 45.6% women), we measured plasma dp-uc MGP , using an ELISA -based assay. We derived central pulse pressure and carotid-femoral pulse wave velocity (PWV) from applanation tonometry and calculated forward and backward pulse waves using an automated, pressure-based wave separation analysis algorithm. Aortic PWV (n=657), central pulse pressure, forward pulse wave, and backward pulse wave mean± SD values were 7.34±1.64 m/s, 45.2±15.3 mm Hg, 33.2±10.2 mm Hg, and 21.8±8.6 mm Hg, respectively. The geometric mean plasma concentration of dp-uc MGP was 4.09 μg/L. All hemodynamic indexes increased across tertiles of dp-uc MGP distribution. In multivariable-adjusted analyses, a doubling of dp-uc MGP was associated with higher PWV (0.15 m/s; 95% CI, 0.01-0.28 m/s), central pulse pressure (1.70 mm Hg; 95% CI, 0.49-2.91 mm Hg), forward pulse wave (0.93 mm Hg; 95% CI, 0.01-1.84 mm Hg), and backward pulse wave (0.71 mm Hg; 95% CI, 0.11-1.30 mm Hg). Categorization of aortic PWV by tertiles of its distribution highlighted a decreasing trend of PWV at low dp-uc MGP (<3.35 μg/L) and an increasing trend at high dp-uc MGP (≥5.31 μg/L). Conclusions In people representative for the general population, higher inactive dp-uc MGP was associated with greater PWV , central pulse pressure, forward pulse wave, and backward pulse wave. These observations highlight new avenues for preserving vascular integrity and preventing cardiovascular complications (eg, by improving a person's vitamin K status).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.119.011960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6509723PMC
April 2019

Vitamin K-Dependent Matrix Gla Protein as Multifaceted Protector of Vascular and Tissue Integrity.

Hypertension 2019 06;73(6):1160-1169

From the Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, Department of Cardiovascular Sciences (F.-F.W., J.A.S.), University Hospitals Leuven, Belgium.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.12412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510326PMC
June 2019

Long-term follow-up of biomarkers of vascular calcification after switch from traditional hemodialysis to online hemodiafiltration.

Scand J Clin Lab Invest 2019 May 18;79(3):174-181. Epub 2019 Feb 18.

d Department of Clinical Chemistry and Department of Clinical and Experimental Medicine , Linköping University , Linköping , Sweden.

Rapid progression of vascular calcification (VC) in hemodialysis (HD) patients is caused by several factors including inflammation and an imbalance between active inducers and inhibitors of VC. Growing evidence shows that online hemodiafiltration (ol-HDF), a combination of diffusive and convective solute transport, has positive effects on the uremic environment that affects patients on dialysis. However, we recently reported that serum 25-hydroxyvitamin D (25(OH)D) decreased after a switch from HD to ol-HDF. As a consequence of this finding, the present study was undertaken to investigate if inducers and inhibitors of VC (i.e. the inactive matrix Gla protein fractions dp-ucMGP and t-ucMGP, fetuin-A, Gla-rich protein (GRP), osteopontin (OPN), bone-specific alkaline phosphatase (BALP), and osteoprotegerin (OPG)) also are affected by ol-HDF. This non-comparative prospective study comprised 35 prevalent patients who were investigated 6, 12, and 24 months after their switch from HD to ol-HDF. Most patients had increased levels of the calcification inhibitors OPN and OPG; and of the inactive calcification inhibitor dp-ucMGP during the study period irrespective of the dialysis modality. BALP and t-ucMGP were mostly within the reference interval, but fetuin-A was mostly below the reference interval during the study period. OPN was significantly associated with BALP and parathyroid hormone, r = 0.62 and r = 0.65 (p < .001), respectively. In conclusion, in contrast to decreased 25(OH)D levels, no differences were found for any of the measured biomarkers of VC following the switch from HD to ol-HDF. Further studies are needed to elucidate how these biomarkers can contribute to calcification risk assessment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/00365513.2019.1576218DOI Listing
May 2019

Inactive matrix Gla protein is a novel circulating biomarker predicting retinal arteriolar narrowing in humans.

Sci Rep 2018 10 10;8(1):15088. Epub 2018 Oct 10.

Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.

Active matrix Gla protein (MGP), a potent inhibitor of calcification in large arteries, protects against macrovascular complications. Recent studies suggested that active MGP helps maintaining the integrity of the renal and myocardial microcirculation, but its role in preserving the retinal microcirculation remains unknown. In 935 randomly recruited Flemish participants (mean age, 40.9 years; 50.3% women), we measured plasma desphospho-uncarboxylated MGP (dp-ucMGP), a marker of poor vitamin K status using an ELISA-based assay at baseline (1996-2010) and retinal microvascular diameters using IVAN software (Vasculomatic ala Nicola, version 1.1) including the central retinal arteriolar (CRAE) and venular (CRVE) equivalent and the arteriole-to-venule ratio (AVR) at follow-up (2008-2015). CRAE (P = 0.005) and AVR (P = 0.080) at follow-up decreased across tertiles of the dp-ucMGP distribution. In unadjusted models, for a doubling of dp-ucMGP at baseline, CRAE and AVR at follow-up respectively decreased by 1.40 µm (95% confidence interval [CI], 0.32 to 2.48; P = 0.011) and 0.006 (CI, 0.001 to 0.011; P = 0.016). In multivariable-adjusted models accounting for sex, baseline characteristics and follow-up duration, these estimates were -1.03 µm (CI, -1.96 to -0.11; P = 0.028) and -0.007 (CI, -0.011 to -0.002; P = 0.007). Additional adjustment for changes from baseline to follow-up in major baseline characteristics yielded as estimates -0.91 µm (CI, -1.82 to -0.01; P = 0.048) and -0.006 (95% CI, -0.011 to -0.001; P = 0.014), respectively. Circulating inactive dp-ucMGP is a long-term predictor of smaller retinal arteriolar diameter in the general population. Our observations highlight the possibility that vitamin K supplementation might promote retinal health.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-33257-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180139PMC
October 2018

Matrix Gla Protein, Plaque Stability, and Cardiovascular Events in Patients with Severe Atherosclerotic Disease.

Cardiology 2018 10;141(1):32-36. Epub 2018 Oct 10.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.

Objective: This study aims to investigate whether plasma matrix Gla protein (MGP) species, desphospho-uncarboxylated (dp-uc) MGP, and total uncarboxylated (t-uc) MGP are associated with plaque levels of uncarboxylated (uc) MGP, markers of plaque stability, and cardiovascular disease (CVD) risk.

Methods: From the Athero-Express biobank, we selected carotid plaque samples of 100 patients who underwent carotid endarterectomy. The level of agreement between plasma MGP species and plaque ucMGP levels was assessed using weighted kappa (κ). We analyzed histological characteristics of plaque composition (plaque hemorrhage, lipid and calcification content). Logistic regression analyses were used to assess the association between plasma MGP and plaque characteristics. Furthermore, CVD endpoints (n = 20) were collected over a mean follow-up of 2.6 years.

Results: Weighted κ statistics of plasma dp-ucMGP and t-ucMGP and plaque ucMGP were 0.10 (95% CI -0.31 to 0.52) and 0.14 (95% CI -0.20 to 0.48). Higher dp-ucMGP levels tended to be associated with less plaque hemorrhage (ORper 500 nM 0.96; 95% CI 0.92-1.00). No association was found for lipid and calcification content. Cox proportional hazards models showed no association between dp-ucMGP (HRper 200 pM 0.92; 95% CI 0.75-1.11) and an inverse association between t-ucMGP (HRper 500 nM 0.79; 95% CI 0.62-0.99) and cardiovascular events.

Conclusions: Plasma dp-ucMGP and t-ucMGP concentrations do not reflect plaque ucMGP levels. Elevated dp-ucMGP levels may be associated with less plaque hemorrhage, suggestive of more stable plaques. T-ucMGP was not related with markers of plaque stability; however, elevated plasma t-ucMGP levels were associated with a reduced CVD risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000493006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390448PMC
November 2019

Aldosterone, inactive matrix gla-protein, and large artery stiffness in hypertension.

J Am Soc Hypertens 2018 09 30;12(9):681-689. Epub 2018 Jun 30.

National Institute of Aging, Baltimore, MD, USA.

Vascular calcification leads to increased large artery stiffness. Matrix gla-protein (MGP) is a vitamin K-dependent protein that inhibits arterial calcification. Aldosterone promotes vascular calcification and stiffness, but the relationships between aldosterone, MGP, and arterial stiffness are unknown. We studied 199 adults (predominantly older men) with hypertension. We assessed the relationship between levels of dephospho-uncarboxylated MGP (dp-ucMGP), aldosterone, and carotid-femoral pulse wave velocity (CF-PWV) using standard regression and mediation analyses. Plasma aldosterone was measured in a subgroup of subjects (n = 106). Aldosterone was strongly associated with dp-ucMGP (standardized β = 0.50, P < .001), which was independent of potential confounders (β = 0.37, P < .001). Levels of dp-ucMGP were significantly associated with CF-PWV (β = 0.30; P < .001), which persisted after adjustment for potential confounders (β = 0.25; P = .004). Plasma aldosterone was also significantly associated with CF-PWV (standardized β = 0.21; P = .035). However, in a model that included aldosterone and dp-ucMGP, only the latter was associated with CF-PWV. Mediation analyses demonstrated a significant dp-ucMGP-mediated effect of aldosterone on CF-PWV, without a significant direct (dp-ucMGP independent) effect. Our study demonstrates a novel independent association between high aldosterone levels and dp-ucMGP, suggesting that aldosterone may influence the MGP pathway. This relationship appears to underlie the previously documented relationship between aldosterone and increased arterial stiffness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jash.2018.06.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6139275PMC
September 2018

Inactive Matrix Gla Protein, Arterial Stiffness, and Endothelial Function in African American Hemodialysis Patients.

Am J Hypertens 2018 05;31(6):735-741

Georgia Prevention Institute, Department of Population Health Sciences, Medical College of Georgia, Augusta University, Augusta, Georgia, USA.

Background: Matrix Gla protein (MGP) is a vascular calcification inhibitor dependent upon vitamin K for activation. Evidence suggests that elevated plasma inactive MGP levels (desphospho-uncarboxylated MGP, dp-ucMGP; indicating poorer vascular vitamin K status) are associated with greater cardiovascular disease (CVD) risk. Despite African Americans experiencing highest rates of kidney failure and CVD events, relationships between dp-ucMGP and CVD risk markers have not been examined in this population. We investigated vascular vitamin K status (via plasma dp-ucMGP) between African American hemodialysis (HD) patients and healthy controls, and the associations of dp-ucMGP with arterial stiffness and endothelial function in HD patients only.

Methods: In 37 African American HD patients and 37 age- and race-matched controls, plasma dp-ucMGP was measured by enzyme immunoassay as a marker of vascular vitamin K status. Carotid-femoral pulse wave velocity (PWV; arterial stiffness measurement) and brachial artery flow-mediated dilation (FMD; endothelial function measurement) were assessed by applanation tonometry and ultrasound, respectively, in HD patients only.

Results: Mean dp-ucMGP levels were 5.6 times higher in HD patients vs. controls (2,139 ± 1,102 vs. 382 ± 181 pmol/l, P < 0.01). Multiple linear regression, adjusting for age, sex, dialysis vintage, diabetes mellitus, CVD history, body mass index, and blood pressure, revealed that dp-ucMGP was independently related to PWV (standardized β = 0.49) and FMD (standardized β = -0.53) (both P < 0.01).

Conclusions: Our data suggest that the higher plasma dp-ucMGP concentrations found in African American HD patients may be associated with greater arterial stiffness and endothelial dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ajh/hpy049DOI Listing
May 2018

Menaquinone Content of Cheese.

Nutrients 2018 Apr 4;10(4). Epub 2018 Apr 4.

R&D Group VitaK, Maastricht University, Oxfordlaan 55, 6229 EV Maastricht, The Netherlands.

Vitamin K₂ (menaquinone) concentrations were measured in a wide range of cheeses and the effects of fat content, ripening and origin of the cheeses were investigated. Moreover, the menaquinone content of cheese was compared with that of other foods known to contain vitamin K₂. It was found that cheese and curd are the most important sources of long-chain menaquinones in the Western diet and, in general, hard cheeses are richer in menaquinones than soft cheeses. However, the actual menaquinone content varies substantially and is dependent on the type of cheese, the time of ripening, the fat content and the geographic area where the cheeses are produced. Given the fact that poor vitamin K status has been mentioned as a risk factor for cardiovascular disease and mortality, while there is no clear evidence for adverse cardiovascular effects of dairy fats, cheese should be considered as a recommendable component in a heart-healthy diet.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/nu10040446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946231PMC
April 2018

Ucma/GRP inhibits phosphate-induced vascular smooth muscle cell calcification via SMAD-dependent BMP signalling.

Sci Rep 2018 03 21;8(1):4961. Epub 2018 Mar 21.

Department of Biochemistry, School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands.

Vascular calcification (VC) is the process of deposition of calcium phosphate crystals in the blood vessel wall, with a central role for vascular smooth muscle cells (VSMCs). VC is highly prevalent in chronic kidney disease (CKD) patients and thought, in part, to be induced by phosphate imbalance. The molecular mechanisms that regulate VC are not fully known. Here we propose a novel role for the mineralisation regulator Ucma/GRP (Upper zone of growth plate and Cartilage Matrix Associated protein/Gla Rich Protein) in phosphate-induced VSMC calcification. We show that Ucma/GRP is present in calcified atherosclerotic plaques and highly expressed in calcifying VSMCs in vitro. VSMCs from Ucma/GRP mice showed increased mineralisation and expression of osteo/chondrogenic markers (BMP-2, Runx2, β-catenin, p-SMAD1/5/8, ALP, OCN), and decreased expression of mineralisation inhibitor MGP, suggesting that Ucma/GRP is an inhibitor of mineralisation. Using BMP signalling inhibitor noggin and SMAD1/5/8 signalling inhibitor dorsomorphin we showed that Ucma/GRP is involved in inhibiting the BMP-2-SMAD1/5/8 osteo/chondrogenic signalling pathway in VSMCs treated with elevated phosphate concentrations. Additionally, we showed for the first time evidence of a direct interaction between Ucma/GRP and BMP-2. These results demonstrate an important role of Ucma/GRP in regulating osteo/chondrogenic differentiation and phosphate-induced mineralisation of VSMCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-23353-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862840PMC
March 2018

Epidemiological and histological findings implicate matrix Gla protein in diastolic left ventricular dysfunction.

PLoS One 2018 12;13(3):e0193967. Epub 2018 Mar 12.

Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.

Objectives: A novel paradigm of diastolic left ventricular (LV) dysfunction proposes involvement of the cardiac microvasculature. Vitamin K dependent matrix Gla protein (MGP) plays a role in preserving microcirculatory integrity. We hypothesized that LV filling pressure-a measure of diastolic LV dysfunction-increases with higher plasma level of inactive desphospho-uncarboxylated MGP (dp-ucMGP). We also studied the distribution of active and inactive MGP in human myocardium.

Methods: We measured echocardiographic diastolic LV function and plasma dp-ucMGP (ELISA) in 668 Flemish and for replication in 386 Swiss.

Results: Among Flemish and Swiss, E/e' (6.78 vs. 6.73) and dp-ucMGP (3.94 μg/L vs. 4.20 μg/L) were similarly distributed. In multivariable-adjusted models, for each doubling of dp-ucMGP, E/e' increased by 0.26, 0.33 and 0.31 in Flemish, Swiss and both cohorts combined (P≤0.026); the odds ratios for having E/e' ≥ 8.5 were 1.99, 3.29 and 2.36, respectively (P≤0.017). Cardiac biopsies from patients with ischemic or dilated cardiomyopathy and healthy hearts (n = 4 for each) were stained with conformation-specific MGP antibodies. In diseased compared with normal hearts, uncarboxylated inactive MGP was more prevalent (P≤0.004) in the perivascular matrix and interstitium (204.4 vs. 8.6 μm2 per field) and phosphorylated active MGP in and around capillaries and interstitial cells (31.3 vs. 6.6 number of positive capillaries and cells per field).

Conclusions: Our study supports a role of activated MGP in maintaining myocardial integrity and diastolic LV performance and can potentially be translated into new strategies for managing diastolic LV dysfunction and preventing its progression to heart failure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193967PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846787PMC
June 2018

Desphospho-Uncarboxylated Matrix-Gla Protein Is Increased Postoperatively in Cardiovascular Risk Patients.

Nutrients 2018 Jan 5;10(1). Epub 2018 Jan 5.

Institution of Clinical Science Lund, Medical Faculty, Lund University, S-22185 Lund, Sweden.

Background: Matrix Gla protein (MGP) is an extrahepatic protein that is dependent on glutamate carboxylation, a vitamin K-dependent process. Its dysfunctional form, desphospho-uncarboxylated-MGP, has been associated with increased arterial calcification and stiffness. The aim of this study was to measure the degree of postoperative carboxylation of MGP and two other Gla proteins in patients scheduled for abdominal or orthopaedic surgery.

Methods: Forty patients undergoing abdominal or orthopaedic surgery were included. Blood samples were collected preoperatively and four days after the surgery. Desphospho-carboxylated MGP (dp-cMGP), desphospho-uncarboxylated MGP (dp-ucMGP), carboxylated osteocalcin (OC) (cOC), uncarboxylated OC (ucOC), and uncarboxylated prothrombin (PIVKA-II) were analysed.

Results: Preoperatively, 29 patients had dp-ucMGP levels above the reference values. Patients with pre-existing cardiovascular comorbidities had higher dp-ucMGP preoperatively compared with patients with no record of cardiovascular disease. Postoperatively, this number increased to 36 patients, and median dp-ucMGP levels increased ( < 0.0001) and correlated to a PIVKA-II increase ( = 0.44). On the other hand, dp-cMGP levels did not significantly alter. Decreased levels of ucOC and cOC were seen after surgery ( = 0.017 and = 0.0033, respectively). Comorbidities, possible nutritional defects, and complications affecting Gla protein activity and function were identified.

Conclusions: Dp-ucMGP was high preoperatively, and had further increased postoperatively. This pattern was linked to several comorbidities, possible nutritional defects, and postoperative complications, which motivates further research about potential interactions between perioperative corrective treatments with vitamin K supplements, cardiovascular biomarkers, and incidents of stroke and myocardial infarction events.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/nu10010046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5793274PMC
January 2018

Chronic Kidney Disease Circulating Calciprotein Particles and Extracellular Vesicles Promote Vascular Calcification: A Role for GRP (Gla-Rich Protein).

Arterioscler Thromb Vasc Biol 2018 03 4;38(3):575-587. Epub 2018 Jan 4.

From the Centre of Marine Sciences (C.S.B.V., L.S., D.C.S.), GenoGla Diagnostics, Centre of Marine Sciences (C.S.B.V., D.C.S.), and Department of Biomedical Sciences and Medicine (A.P.S., P.L.N.), University of Algarve, Faro, Portugal; UCIBIO-REQUIMTE, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Caparica, Portugal (A.L.M., R.M.); Centro de Investigação Interdisciplinar Egas Moniz, Egas Moniz-Cooperativa de Ensino Superior CRL, Caparica, Portugal (A.A.M.); Nephrology Department, Centro Hospitalar do Algarve, Faro, Portugal (A.P.S., P.L.N.); VIB-UGent Center for Medical Biotechnology Center and UGent Department of Biochemistry, Ghent, Belgium (A.S., K.G.); and R&D Group VitaK (C.V.) and Department of Biochemistry - Vascular Aspects, Faculty of Medicine, Health and Life Science (L.S.), Maastricht University, The Netherlands.

Objective: Inhibition of mineral crystal formation is a crucial step in ectopic calcification. Serum calciprotein particles (CPPs) have been linked to chronic kidney disease (CKD) calcification propensity, but additional knowledge is required to understand their function, assemblage, and composition. The role of other circulating nanostructures, such as extracellular vesicles (EVs) in vascular calcification is currently unknown. Here, we investigated the association of GRP (Gla-rich protein) with circulating CPP and EVs and the role of CKD CPPs and EVs in vascular calcification.

Approach And Results: Biological CPPs and EVs were isolated from healthy and CKD patients and comparatively characterized using ultrastructural, analytic, molecular, and immuno-based techniques. Our results show that GRP is a constitutive component of circulating CPPs and EVs. CKD stage 5 serum CPPs and EVs are characterized by lower levels of fetuin-A and GRP, and CPPs CKD stage 5 have increased mineral maturation, resembling secondary CPP particles. Vascular smooth muscle cell calcification assays reveal that CPPs CKD stage 5 and EVs CKD stage 5 are taken up by vascular smooth muscle cells and induce vascular calcification by promoting cell osteochondrogenic differentiation and inflammation. These effects were rescued by incubation of CPPs CKD stage 5 with γ-carboxylated GRP. In vitro, formation and maturation of basic calcium phosphate crystals was highly reduced in the presence of γ-carboxylated GRP, fetuin-A, and MGP (matrix gla protein), and a similar antimineralization system was identified in vivo.

Conclusions: Uremic CPPs and EVs are important players in the mechanisms of widespread calcification in CKD. We propose a major role for cGRP as inhibitory factor to prevent calcification at systemic and tissue levels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/ATVBAHA.117.310578DOI Listing
March 2018

Prevalence and Effects of Functional Vitamin K Insufficiency: The PREVEND Study.

Nutrients 2017 Dec 8;9(12). Epub 2017 Dec 8.

Top Institute Food and Nutrition, 6709 PA Wageningen, The Netherlands.

Matrix Gla Protein (MGP) is a strong vitamin K-dependent inhibitor of soft tissue calcification. We assessed the prevalence of functional vitamin K insufficiency, as derived from plasma desphospho-uncarboxylated MGP (dp-ucMGP), and investigated whether plasma dp-ucMGP is associated with all-cause and cardiovascular mortality in a large general population-based cohort. We included 4275 subjects (aged 53 ± 12 years, 46.0% male) participating in the prospective general population-based Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. The prevalence of functional vitamin K insufficiency (i.e., dp-ucMGP > 500 pmol/L) was 31% in the total study population. This prevalence was significantly higher among elderly and subjects with comorbidities like hypertension, type 2 diabetes, chronic kidney disease, and cardiovascular disease (~50%). After 10 years of follow-up, 279 subjects had died, with 74 deaths attributable to cardiovascular causes. We found significant J-shaped associations of plasma dp-ucMGP with all-cause (linear term: hazard ratio (HR) (95% confidence interval (CI)) = 0.20 (0.12-0.33), < 0.001; squared term: 1.14 (1.10-1.17), < 0.001) and cardiovascular mortality (linear term: 0.12 (0.05-0.27), < 0.001; squared term: 1.17 (1.11-1.23), < 0.001). These associations remained significant after adjustment for potential confounders. Whether the correction of vitamin K insufficiency improves health outcomes needs to be addressed in future prospective intervention studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/nu9121334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748784PMC
December 2017

Vitamin K deficiency: the linking pin between COPD and cardiovascular diseases?

Respir Res 2017 11 13;18(1):189. Epub 2017 Nov 13.

Department of Pulmonary Medicine, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands.

Cardiovascular diseases are prevalent in patients with chronic obstructive pulmonary disease (COPD). Their coexistence implies that many COPD patients require anticoagulation therapy. Although more and more replaced by direct oral anticoagulants, vitamin K antagonists (VKAs) are still widely used. VKAs induce profound deficiency of vitamin K, a key activator in the coagulation pathway. It is recognized however that vitamin K is also an essential cofactor in the activation of other extrahepatic proteins, such as matrix Gla protein (MGP), a potent inhibitor of arterial calcification. No or insufficient MGP activation by the use of VKAs is associated with a rapid progression of vascular calcification, which may enhance the risk for overt cardiovascular disease. Vitamin K consumption, on the other hand, seems to have a protective effect on the mineralization of arteries. Furthermore, vascular calcification mutually relates to elastin degradation, which is accelerated in patients with COPD associating with impaired survival. In this commentary, we hypothesize that vitamin K is a critical determinant to the rate of elastin degradation. We speculate on the potential link between poor vitamin K status and crucial mechanisms of COPD pathogenesis and raise concerns about the use of VKAs in patients with this disease. Future intervention studies are needed to explore if vitamin K supplementation is able to reduce elastin degradation and vascular calcification in COPD patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12931-017-0673-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5683584PMC
November 2017

Vitamin K deficit and elastolysis theory in pulmonary elasto-degenerative diseases.

Med Hypotheses 2017 Oct 21;108:38-41. Epub 2017 Jul 21.

R&D Group VitaK, Maastricht University, Maastricht, The Netherlands.

Elastin is a unique protein providing deformability and resilience to dynamic tissues, such as arteries and lungs. It is an absolute basic requirement for circulation and respiration. Elastin can be degraded by elastases and has a high calcium affinity. Elastin calcification and elastin degradation are two pathological processes that impair elastin's functioning. Furthermore, elastin degradation can be associated to elastin calcification. Matrix Gla Protein (MGP) is probably the most potent natural inhibitor of elastin calcification and requires vitamin K for its activation. Measuring circulating levels of inactive MGP (dp-ucMGP) is a frequently used method to assess vitamin K status. Dp-ucMGP reflects the burden of vitamin K-dependent proteins that have not been activated by vitamin K and could therefore best be regarded as a biomarker of a vitamin K deficit. Dp-ucMGP levels decrease after vitamin K supplementation. Since the amino acids desmosine and isodesmosine (DES) are unique to crosslinked elastin fibers, systemic elastin degradation can be assessed with the plasma DES assay. Recently, we discovered a strong correlation between plasma dp-ucMGP and plasma DES levels in both patients with chronic obstructive pulmonary disease (COPD) and controls. The 'Vitamin K deficit and elastolysis theory' posits that elastin degradation causes a rise in the vitamin K deficit and implies that vitamin K supplementation could be preventing elastin degradation. If this hypothesis holds true and is universally found in every state and condition, it will have an unprecedented impact on the management of every single pulmonary disease characterized by accelerated elastin degradation, such as alpha-1 antitrypsin deficiency, bronchiectasis, COPD and cystic fibrosis. Theoretically, a plasma dp-ucMGP concentration of zero would be associated with a near-complete standstill of elastin degradation and disease progression in patients with any of these debilitating conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mehy.2017.07.029DOI Listing
October 2017

Desphospho-uncarboxylated matrix Gla protein is a novel circulating biomarker predicting deterioration of renal function in the general population.

Nephrol Dial Transplant 2018 07;33(7):1122-1128

Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.

Background: Recent studies showing an inverse association between estimated glomerular filtration rate (eGFR), a microvascular trait, and inactive desphospho-uncarboxylated matrix Gla protein (dp-ucMGP) support the hypothesis that after vitamin K-dependent activation, matrix Gla protein (MGP) is renoprotective, but these were limited by their cross-sectional design.

Methods: In 1009 randomly recruited Flemish (50.6% women), we assessed the association between eGFR and plasma dp-ucMGP, using multivariable-adjusted analyses.

Results: From baseline to follow-up 8.9 years later (median), dp-ucMGP increased by 23.0% whereas eGFR decreased by 4.05 mL/min/1.73 m2 (P < 0.001). In 938 participants with baseline eGFR ≥60 mL/min/1.73 m2, the incidence of eGFR <60 mL/min/1.73 m2 at follow-up was 8.0% versus 4.1% in the top versus the bottom halve of baseline dp-ucMGP. For a 5-fold higher plasma dp-ucMGP at baseline, eGFR at follow-up decreased by 3.15 mL/min/1.73 m2 [95% confidence interval (CI) 1.26-5.05; P = 0.001]. The hazard ratio expressing the risk of progression to eGFR <60 mL/min/1.73 m2 was 3.49 (95% CI 1.45-8.40; P = 0.005). The hazard ratio relating the presence of microalbuminuria at follow-up to baseline dp-ucMGP was 4.70 (95% CI 1.57-14.1; P = 0.006).

Conclusions: In conclusion, circulating inactive dp-ucMGP, a biomarker of poor vitamin K status, predicts renal dysfunction. Possible underlying mechanisms include protection by activated MGP against calcification and inhibition of the bone morphogenetic protein-signalling pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ndt/gfx258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030862PMC
July 2018

Gla-rich protein function as an anti-inflammatory agent in monocytes/macrophages: Implications for calcification-related chronic inflammatory diseases.

PLoS One 2017 18;12(5):e0177829. Epub 2017 May 18.

Centre of Marine Sciences (CCMAR), University of Algarve, Faro, Portugal.

Calcification-related chronic inflammatory diseases are multifactorial pathological processes, involving a complex interplay between inflammation and calcification events in a positive feed-back loop driving disease progression. Gla-rich protein (GRP) is a vitamin K dependent protein (VKDP) shown to function as a calcification inhibitor in cardiovascular and articular tissues, and proposed as an anti-inflammatory agent in chondrocytes and synoviocytes, acting as a new crosstalk factor between these two interconnected events in osteoarthritis. However, a possible function of GRP in the immune system has never been studied. Here we focused our investigation in the involvement of GRP in the cell inflammatory response mechanisms, using a combination of freshly isolated human leucocytes and undifferentiated/differentiated THP-1 cell line. Our results demonstrate that VKDPs such as GRP and matrix gla protein (MGP) are synthesized and γ-carboxylated in the majority of human immune system cells either involved in innate or adaptive immune responses. Stimulation of THP-1 monocytes/macrophages with LPS or hydroxyapatite (HA) up-regulated GRP expression, and treatments with GRP or GRP-coated basic calcium phosphate crystals resulted in the down-regulation of mediators of inflammation and inflammatory cytokines, independently of the protein γ-carboxylation status. Moreover, overexpression of GRP in THP-1 cells rescued the inflammation induced by LPS and HA, by down-regulation of the proinflammatory cytokines TNFα, IL-1β and NFkB. Interestingly, GRP was detected at protein and mRNA levels in extracellular vesicles released by macrophages, which may act as vehicles for extracellular trafficking and release. Our data indicate GRP as an endogenous mediator of inflammatory responses acting as an anti-inflammatory agent in monocytes/macrophages. We propose that in a context of chronic inflammation and calcification-related pathologies, GRP might act as a novel molecular mediator linking inflammation and calcification events, with potential therapeutic application.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0177829PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5436823PMC
September 2017

Synergistic effect of low K and D vitamin status on arterial stiffness in a general population.

J Nutr Biochem 2017 08 22;46:83-89. Epub 2017 Apr 22.

R&D Group VitaK, Maastricht University, The Netherlands.

Both vitamins K and D are nutrients with pleiotropic functions in human tissues. The metabolic role of these vitamins overlaps considerably in calcium homeostasis. We analyzed their potential synergetic effect on arterial stiffness. In a cross-sectional study, we analyzed aortic pulse wave velocity (aPWV) in 1023 subjects from the Czech post-MONICA study. Desphospho-uncarboxylated matrix γ-carboxyglutamate protein (dp-ucMGP), a biomarker of vitamin K status, was measured by sandwich ELISA and 25-hydroxyvitamin D (25-OH-D) by a commercial immunochemical assay. In a subsample of 431 subjects without chronic disease or pharmacotherapy, we detected rs2228570 polymorphism for the vitamin D receptor. After adjustment for confounders, aPWV was independently associated with both factors: dp-ucMGP [β-coefficient(S.E.M.)=13.91(4.87); P=.004] and 25-OH-D [0.624(0.28); P=.027]. In a further analysis, we divided subjects according to dp-ucMGP and 25-OH-D quartiles, resulting in 16 subgroups. The highest aPWV had subjects in the top quartile of dp-ucMGP plus bottom quartile of 25-OH-D (i.e., in those with insufficient status of both vitamin K and vitamin D), while the lowest aPVW had subjects in the bottom quartile of dp-ucMGP plus top quartile of 25-OH-D [9.8 (SD2.6) versus 6.6 (SD1.6) m/s; P<.0001]. When we compared these extreme groups of vitamin K and D status, the adjusted odds ratio for aPWV≥9.3 m/s was 6.83 (95% CI:1.95-20.9). The aPWV was also significantly higher among subjects bearing the GG genotype of rs2228570, but only in those with a concomitantly poor vitamin K status. In conclusion, we confirmed substantial interaction of insufficient K and D vitamin status in terms of increased aortic stiffness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jnutbio.2017.04.010DOI Listing
August 2017

Circulating Vitamin K Is Inversely Associated with Incident Cardiovascular Disease Risk among Those Treated for Hypertension in the Health, Aging, and Body Composition Study (Health ABC).

J Nutr 2017 05 29;147(5):888-895. Epub 2017 Mar 29.

Sticht Center on Aging, Wake Forest School of Medicine, Winston-Salem, NC.

A role for vitamin K in coronary artery calcification (CAC), a subclinical manifestation of cardiovascular disease (CVD), has been proposed because vitamin K-dependent proteins, including the calcification inhibitor matrix Gla protein (MGP), are present in vascular tissue. Observational studies found that low circulating phylloquinone (vitamin K-1) was associated with increased CAC progression, especially in persons treated for hypertension. It is unknown whether hypertension treatment modifies this putative role of vitamin K in clinical CVD risk. We determined the association between vitamin K status and incident clinical CVD in older adults in the Health ABC (Health, Aging, and Body Composition Study) and whether the association differed by hypertension treatment status. Plasma phylloquinone was measured in 1061 participants free of CVD (70-79 y of age, 58% women, 39% black). Plasma uncarboxylated MGP [(dp)ucMGP] was measured in a subset of 635 participants. Multivariate Cox models estimated the HR for incident CVD over 12.1 follow-up years. Effect modification by hypertension was tested with the use of interaction terms. Neither low plasma phylloquinone (<0.2 nmol/L) nor elevated (dp)ucMGP (≥574 pmol/L) was significantly associated with incident CVD [respective HRs (95% CIs): 1.27 (0.75, 2.13) and 1.02 (0.72, 1.45)]. In participants treated for hypertension ( = 489; 135 events), low plasma phylloquinone was associated with higher CVD risk overall (HR: 2.94; 95% CI: 1.41, 6.13). In those with untreated hypertension ( = 153; 48 events) and without hypertension ( = 418; 92 events), low plasma phylloquinone was not associated with incident CVD. The association between high (dp)ucMGP did not differ by hypertension treatment status (-interaction = 0.72). Vitamin K status was not significantly associated with CVD risk overall, but low plasma phylloquinone was associated with a higher CVD risk in older adults treated for hypertension. Additional evidence from larger clinical studies is needed to clarify the importance of vitamin K to CVD in persons treated for hypertension, a segment of the population at high risk of clinical CVD events.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3945/jn.117.249375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404216PMC
May 2017

The risk of nephrolithiasis is causally related to inactive matrix Gla protein, a marker of vitamin K status: a Mendelian randomization study in a Flemish population.

Nephrol Dial Transplant 2018 03;33(3):514-522

Studies Coordinating Centre, Research Unit of Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.

Background: Vitamin K (VK)-dependent γ-glutamate carboxylation and serine phosphorylation activate matrix Gla protein (MGP) to a potent locally acting inhibitor of calcification. Nephrolithiasis represents a process of unwanted calcification associated with substantial mortality and high recurrence rates. We hypothesized that the risk of nephrolithiasis increases with VK shortage, as exemplified by higher plasma levels of desphospho-uncarboxylated MGP (dp-ucMGP).

Methods: In 1748 randomly recruited Flemish individuals (51.1% women; mean age 46.8 years), we determined dp-ucMGP and the prevalence of nephrolithiasis at baseline (April 1996-February 2015) and its incidence during follow-up until March 2016. We estimated the multivariable-adjusted relative risk associated with the doubling of dp-ucMGP, using logistic or Cox regression. We did a Mendelian randomization analysis using four MGP genotypes as instrumental variables.

Results: With adjustments applied for sex, age and 24-h urinary volume and calcium excretion, the odds of having prevalent nephrolithiasis [n = 144 (8.2%)] associated with dp-ucMGP was 1.31 [95% confidence interval (CI) 1.04-1.64; P = 0.022]. dp-ucMGP levels were associated (P ≤ 0.001) with MGP variants rs2098435, rs4236 and rs2430692. In the Mendelian analysis, the causal odds ratio was 3.82 (95% CI 1.15-12.7; P = 0.029). The incidence of nephrolithiasis over 12.0 years (median) was 37 cases (0.2%). With similar adjustments as before, the hazard ratio in relation to dp-ucMGP was 2.48 (95% CI 1.71-3.61; P < 0.001). Additional adjustment for a nephrolithiasis propensity score produced consistent results.

Conclusion: Higher levels of inactive dp-ucMGP may be causally associated with the risk of nephrolithiasis. Whether or not VK deficiency plays a role in these observations remains to be firmly established.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ndt/gfx014DOI Listing
March 2018