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Relationship of matrix Gla protein and vitamin K with vascular calcification in hemodialysis patients.

ABSTRACT: Objective: This study evaluated associations of serum matrix Gla protein (MGP), plasma vitamin K1, and plasma vitamin K2 with coronary artery calcium score (CACS) and cardiovascular disease (CVD) in maintenance hemodialysis (MHD) patients. Methods: Subjects comprised 112 MHD patients aged 30-60 years and 40 age-matched healthy subjects. Total MGP, vitamin K1, vitamin K2, and lipid profile were examined in all subjects; other clinical data, medication use, and CACS were assessed only in MHD patients. Determinants of MGP in all subjects were identified by regression analysis. Factors associated with CACS and CVD in MHD patients were identified by regression analysis and logistic analysis, respectively. Results: Lower plasma levels of vitamin K1 corrected for triglycerides [0.39 (0.24-0.70) vs. 0.77 (0.48-1.34) ng/mg, p < 0.001], higher frequency of plasma vitamin K2 ≤ 0.05 ng/ml (p = 0.23), and higher serum total MGP (288.4 ± 44.2 vs. 159.7 ± 40.6 ng/ml, p < 0.0001) were observed in MHD patients than in healthy controls. Total MGP level was significantly associated with levels of vitamin K1 corrected for triglycerides (p <0 .001) and vitamin K2 ≤ 0.05 ng/ml (p < 0.05) in all subjects. Total MGP level was significantly associated with presence of CVD (p <0 .05), but not CACS, in MHD patients. Conclusion: The end-stage renal disease on hemodialysis is a deficiency state of vitamin K. Total MGP was significantly higher in MHD patients compared to healthy subjects and total MGP was associated with the presence of CVD, but not CACS, in MHD patients.

SUBMITTER: Mizuiri S

PROVIDER: S-EPMC7011966 | biostudies-literature |

REPOSITORIES: biostudies-literature

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

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

| S-EPMC7193028 | biostudies-literature

Quercetin attenuates warfarin-induced vascular calcification in vitro independently from matrix Gla protein.

Project description:Warfarin can stimulate vascular calcification in vitro via activation of ?-catenin signaling and/or inhibition of matrix Gla protein (MGP) carboxylation. Calcification was induced in vascular smooth muscle cells (VSMCs) with therapeutic levels of warfarin in normal calcium and clinically acceptable phosphate levels. Although TGF/BMP and PKA pathways are activated in calcifying VSMCs, pharmacologic analysis reveals that their activation is not contributory. However, ?-catenin activity is important because inhibition of ?-catenin with shRNA or bioflavonoid quercetin prevents calcification in primary human VSMCs, rodent aortic rings, and rat A10 VSMC line. In the presence of quercetin, reactivation of ?-catenin using the glycogen synthase kinase-3? (GSK-3?) inhibitor LiCl restores calcium accumulation, confirming that quercetin mechanism of action hinges on inhibition of the ?-catenin pathway. Calcification in VSMCs induced by 10 ?m warfarin does not associate with reduced levels of carboxylated MGP, and inhibitory effects of quercetin do not involve induction of MGP carboxylation. Further, down-regulation of MGP by shRNA does not alter the effect of quercetin. These results suggest a new ?-catenin-targeting strategy to prevent vascular calcification induced by warfarin and identify quercetin as a potential therapeutic in this pathology.

| S-EPMC3554930 | biostudies-literature

The relationship between intradialytic hypotension and vascular calcification in hemodialysis patients.

Project description:BackgroundVascular calcification is associated with structural and functional abnormality of the heart and blood vessels. We investigated the relationship between intradialytic hypotension (IDH) and vascular calcification in hemodialysis (HD) patients, and their impacts on cardiovascular events (CVEs).MethodWe enrolled 191 maintenance HD patients who underwent plain abdomen radiography for abdominal aortic calcification score (AACS). A nadir systolic blood pressure (BP) < 90 mm Hg or the requirement of bolus fluid administration was required to quantify the hypotension diagnosis. IDH was defined as > 2 hypotension episodes during 10 HD treatments.ResultsAmong the 191 patients, IDH occurred in 32. AACS was higher in the IDH group compared with the no-IDH group (8.4 ± 6.0 vs. 4.9 ± 5.2, respectively; P = 0.001). High AACS was an independent risk factor after adjustment for age, diabetes mellitus, ultrafiltration, diastolic BP, and calcium level (odds ratio (OR) = 1.09, 95% CI = 1.01-1.18; P = 0.03). Patients with both IDH and AACS ≧ 4 had the highest cumulative CVE rate (27.9%, P = 0.008) compared with 11.2%, 12.5%, and 6% for those with AACS ≧ 4 only, with IDH only, and neither, respectively. In multivariate analysis, the presence of both IDH and AACS ≧ 4 was a significant predictor of CVE (hazard ratio (HR) = 2.84, 95% CI = 1.04-7.74, P = 0.04).ConclusionIDH is associated with abdominal aortic calcification and is an independent risk factor for IDH. Both IDH and high AACS were significant predictors of CVE.

| S-EPMC5648120 | biostudies-literature

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

Project description: Not available

| S-EPMC6510326 | biostudies-literature

Inhibition of bone morphogenetic protein signal transduction prevents the medial vascular calcification associated with matrix Gla protein deficiency.

Project description:ObjectiveMatrix Gla protein (MGP) is reported to inhibit bone morphogenetic protein (BMP) signal transduction. MGP deficiency is associated with medial calcification of the arterial wall, in a process that involves both osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) and mesenchymal transition of endothelial cells (EndMT). In this study, we investigated the contribution of BMP signal transduction to the medial calcification that develops in MGP-deficient mice.Approach and resultsMGP-deficient mice (MGP(-/-)) were treated with one of two BMP signaling inhibitors, LDN-193189 or ALK3-Fc, beginning one day after birth. Aortic calcification was assessed in 28-day-old mice by measuring the uptake of a fluorescent bisphosphonate probe and by staining tissue sections with Alizarin red. Aortic calcification was 80% less in MGP(-/-) mice treated with LDN-193189 or ALK3-Fc compared with vehicle-treated control animals (P<0.001 for both). LDN-193189-treated MGP(-/-) mice survived longer than vehicle-treated MGP(-/-) mice. Levels of phosphorylated Smad1/5 and Id1 mRNA (markers of BMP signaling) did not differ in the aortas from MGP(-/-) and wild-type mice. Markers of EndMT and osteogenesis were increased in MGP(-/-) aortas, an effect that was prevented by LDN-193189. Calcification of isolated VSMCs was also inhibited by LDN-193189.ConclusionsInhibition of BMP signaling leads to reduced vascular calcification and improved survival in MGP(-/-) mice. The EndMT and osteogenic transdifferentiation associated with MGP deficiency is dependent upon BMP signaling. These results suggest that BMP signal transduction has critical roles in the development of vascular calcification in MGP-deficient mice.

| S-EPMC4300181 | biostudies-literature

Fetuin, matrix-Gla protein and osteopontin in calcification of renal allografts.

Project description:BackgroundCalcification of renal allografts is common in the first year after transplantation and is related to hyperparathyroidism. It is associated with an impaired long-term function of the graft (Am J Transplant 5?1934-41, 2005). Aim of this study is to examine the role of the anti-calcifying/calcifying factors in the pathophysiology of renal allograft calcification.MethodsWe analyzed protocol allograft biopsies, blood and urine samples of 31 patients with and 27 patients without allograft calcification taken at 6 weeks, 3 and 6 months after transplantation. Patient demographical data, cold ischemia time, initial graft function and donor characteristics were comparable between the two groups. Biopsies were stained for osteopontin, fetuin, and matrix-gla-protein. Serum and urine electrolytes, matrix-gla-protein, fetuin, Vitamin D and intact parathyroid hormone in serum and osteopontin (OPN) in urine were examined.ResultsSerum levels of fetuin and matrix-Gla protein as well as urinary levels of OPN showed specific time dependent changes (6 weeks vs. 3 months vs. 6 months; all p<0.0001). In patients with calcifications, urinary levels of OPN were decreased by 55% at 6 weeks and increased thereafter, showing 54% higher levels at 6 months compared to patients without calcification (6 weeks: p<0.01, 6 months: p<0.05). Local protein expression of fetuin-A, matrix-Gla protein and OPN in the graft was specifically increased around calcified plaques, without differences in the mRNA tissue expression.ConclusionAnticalcifying factors show significant changes in the early phase after renal transplantation, which may be important for the prevention of allograft calcification. The differences in OPN indicate an involvement of this factor in the regulation of calcification.

| S-EPMC3524113 | biostudies-literature

Matrix Gla protein is an independent predictor of both intimal and medial vascular calcification in chronic kidney disease.

Project description:Matrix Gla protein (MGP) is a potent inhibitor of vascular calcification (VC) and requires carboxylation by vitamin K to exert calcification inhibition. Chronic kidney disease (CKD) patients undergo early vascular aging often involving extensive VC. The present cross-sectional study investigated the association between circulating dp-ucMGP levels, MGP expression in vascular tissue and MGP polymorphisms. In 141 CKD stage 5 patients, CAC score was significantly increased in the highest tertile of dp-ucMGP (p?=?0.002), and a high medial VC score was associated with elevated dp-ucMGP levels. MGP vascular expression was associated with increased circulating dp-ucMGP and CAC scores. MGP SNP analysis revealed that patients homozygous for the C allele of the rs1800801 variant had a higher CAC score (median 15 [range 0-1312]) compared to patients carrying a T allele (median 0 [range 0-966] AU). These results indicate that plasma levels of dp-ucMGP are an independent predictor of increased VC in CKD5 patients and correlate with both higher CAC scores and degree of medial calcification. Additionally, high vascular expression of MGP was associated with higher CAC scores and plasma dp-ucMGP levels. Taken together, our results support that MGP is involved in the pathogenesis of VC.

| S-EPMC7171129 | biostudies-literature

Association of Matrix Gla protein gene (rs1800801, rs1800802, rs4236) polymorphism with vascular calcification and atherosclerotic disease: a meta-analysis.

Project description:Association between the MGP gene rs1800801, rs1800802, rs4236 polymorphisms and vascular calcification and atherosclerotic disease was inconsistent. To clarify precise association, we performed this meta-analysis. Medline, Embase and China Knowledge Resource Integrated Database were systematically searched through December 2016. A total of 23 case-control studies, consisting of 5280 cases and 5773 controls, were included. The overall results suggested that the -7A polymorphism was associated with an increased risk for vascular calcification and atherosclerotic disease in the recessive model (OR?=?1.50, 95% CI 1.01-2.24, P?=?0.045). Subgroup analyses of Caucasians showed significant associations in the allelic model, recessive model, and homozygote model: allelic model (OR?=?1.19, 95% CI 1.06-1.34, P?=?0.004), recessive model (OR?=?1.60, 95% CI 1.26-2.03, P?<?0.001), homozygote model (OR?=?1.83, 95% CI 1.18-2.81, P?=?0.006). Subgroup analysis of the Asian population did not demonstrate any significant associations in any of the genetic models. No significant association was found in any genetic model amongst the rs1800802 and rs4236 polymorphisms. The findings of this meta-analysis indicate that the MGP gene rs1800801 polymorphism is significantly associated with vascular calcification and atherosclerotic disease, especially in the Caucasian population.

| S-EPMC5562806 | biostudies-literature

Matrix Gla protein polymorphisms are associated with coronary artery calcification in men.

Project description:Matrix Gla protein (MGP) is a key regulator of vascular calcification. Genetic variation at the MGP locus could modulate the development of coronary artery calcification (CAC). Our aim was to examine the cross-sectional association between MGP single nucleotide polymorphisms (SNPs) [rs1800802 (T-138C), rs1800801 (G-7A), and rs4236 (Ala102Thr)] and CAC. CAC was measured by multidetector computed tomography (MDCT), in older men and women of European descent, (n=386; 60 to 80 y of age). Serum MGP was measured by radioimmunoassay. Linear, Tobit and Ordinal regression analyses all revealed that in men, homozygous carriers of the minor allele of rs1800802, rs1800801, or rs4236 (minor allele frequency: 21, 38, and 40%, respectively) were associated with a decreased quantity of CAC, relative to major allele carriers. This association was not found in women. Although genetic variation in MGP was associated with serum MGP concentrations, there were no associations between serum MGP and CAC. The results of this study suggest a role for MGP genetic variants in coronary atherosclerosis among men that is not reflected in serum MGP concentrations.

| S-EPMC2706526 | biostudies-literature

Matrix gla protein gene polymorphism is associated with increased coronary artery calcification progression.

Project description:ObjectiveMatrix gla protein (MGP) inhibits arterial and cartilaginous calcification. A threonine to alanine (Thr83Ala) polymorphism (codon 83) in MGP is associated with myocardial infarction and femoral artery calcification. We examined the association of the MGP Thr83Ala polymorphism with quantity and progression of coronary artery calcification (CAC), a noninvasive measure of subclinical coronary atherosclerosis.Methods and resultsIn 605 participants of the Epidemiology of Coronary Artery Calcification Study, generalized linear mixed models were fit to determine the association of MGP Thr83Ala with CAC quantity and progression. There was a significant additive relation between MGP Thr83Ala and CAC progression (P=0.001). In the fully adjusted model, every 1 Ala83 allele increase was associated with an estimated 1.9% (95% confidence interval, 0.7%-3.0%) per year since baseline larger increase in CAC quantity. A proxy single nucleotide polymorphism for MGP Thr83Ala (rs6488724) was similarly associated with CAC progression in an independent cohort from the Genetic Epidemiology Network of Arteriopathy (GENOA) study.ConclusionsIncreased risk of myocardial infarction associated with MGP ThrAla83 genotype observed elsewhere may be related to faster progression of subclinical coronary atherosclerosis. MGP genotype could be a potential candidate for identifying individuals at increased risk of atherosclerotic disease who would benefit from aggressive primary prevention strategies.

| S-EPMC3586431 | biostudies-literature

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