Vitamin K-Dependent Matrix Gla Protein as Multifaceted Protector of Vascular and Tissue Integrity.
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ABSTRACT:
SUBMITTER: Wei FF
PROVIDER: S-EPMC6510326 | biostudies-literature | 2019 Jun
REPOSITORIES: biostudies-literature
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Vitamin K-Dependent Matrix Gla Protein as Multifaceted Protector of Vascular and Tissue Integrity.
Wei Fang-Fei FF Trenson Sander S Verhamme Peter P Vermeer Cees C Staessen Jan A JA
Hypertension (Dallas, Tex. : 1979) 20190601 6
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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.
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Project description: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.
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Project description:Matrix Gla protein (MGP) is a potent inhibitor of vascular calcification. The ability of MGP to inhibit calcification requires the activity of a vitamin K-dependent enzyme, which mediates MGP carboxylation. We investigated how MGP carboxylation influences the risk of calciphylaxis in adult patients receiving dialysis and examined the effects of vitamin K deficiency on MGP carboxylation. Our study included 20 patients receiving hemodialysis with calciphylaxis (cases) and 20 patients receiving hemodialysis without calciphylaxis (controls) matched for age, sex, race, and warfarin use. Cases had higher plasma levels of uncarboxylated MGP (ucMGP) and carboxylated MGP (cMGP) than controls. However, the fraction of total MGP that was carboxylated (relative cMGP concentration = cMGP/[cMGP + uncarboxylated MGP]) was lower in cases than in controls (0.58±0.02 versus 0.69±0.03, respectively; P=0.003). In patients not taking warfarin, cases had a similarly lower relative cMGP concentration. Each 0.1 unit reduction in relative cMGP concentration associated with a more than two-fold increase in calciphylaxis risk. Vitamin K deficiency associated with lower relative cMGP concentration in multivariable adjusted analyses (β=-8.99; P=0.04). In conclusion, vitamin K deficiency-mediated reduction in relative cMGP concentration may have a role in the pathogenesis of calciphylaxis. Whether vitamin K supplementation can prevent and/or treat calciphylaxis requires further study.
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Project description:To investigate matrix gla protein (Mgp) function in angiogenesis and adipogenesis in brown adipose tissue (BAT) of C57BL/6 mice. we dissected 5 pairs of BAT from 4 weeks male Mgp wild-type (WT) and knock out (KO) mice. We then performed gene expression profiling analysis using data obtained from RNA-seq of 5 pairs of WT and KO mice.
2025-06-28 | GSE233274 | GEO
Project description:Warfarin can stimulate vascular calcification in vitro via activation of β-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, β-catenin activity is important because inhibition of β-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 β-catenin using the glycogen synthase kinase-3β (GSK-3β) inhibitor LiCl restores calcium accumulation, confirming that quercetin mechanism of action hinges on inhibition of the β-catenin pathway. Calcification in VSMCs induced by 10 μm 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 β-catenin-targeting strategy to prevent vascular calcification induced by warfarin and identify quercetin as a potential therapeutic in this pathology.
| S-EPMC3554930 | biostudies-literature
Project description:Matrix Gla Protein (MGP) is an ECM molecule commonly associated with dysfunctions of large blood vessels such as arteriosclerosis and atherosclerosis. However, the exact role of MGP in the microvasculature is not clear. Utilizing a mouse MGP knockout model we found that MGP suppresses angiogenic sprouting from mouse aorta restricts microvascular density in cardiac and skeletal muscle, and is an endogenous inhibitor of tumor angiogenesis. Similarly, morpholino based knockdown of MGP in zebrafish embryos caused a progressive loss of luminal structures in intersegmental vessels, a phenotype reminiscent of Dll4/Notch inhibition. Accordingly, MGP suppressed Notch-dependent Hes-1 promoter activity and expression of Jagged1 mRNA relative to Dll4 mRNA. However, inhibition of BMP but not Notch or VEGF signaling reversed the excessive angiogenic sprouting phenotype of MGP knockout aortic rings suggesting that MGP may normally suppress angiogenic sprouting by blocking BMP signaling. Collectively, these results suggest that MGP is a multi-functional inhibitor of normal and abnormal angiogenesis that may function by coordinating with both Notch and BMP signaling pathways.
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Project description:Vitamin K is essential for activation of ?-carboxyglutamate (Gla)-proteins including the vascular calcification inhibitor matrix Gla-protein (MGP). Insufficient vitamin K intake leads to production of uncarboxylated, mostly inactive proteins and contributes to an increased cardiovascular risk. In kidney transplant recipients, cardiovascular risk is high but vitamin K intake and status have not been defined. We investigated dietary vitamin K intake, vascular vitamin K status and its determinants in kidney transplant recipients. We estimated vitamin K intake in a cohort of kidney transplant recipients (n?=?60) with stable renal function (creatinine clearance 61 [42-77] (median [interquartile range]) ml/min), who were 75 [35-188] months after transplantation, using three-day food records and food frequency questionnaires. Vascular vitamin K status was assessed by measuring plasma desphospho-uncarboxylated MGP (dp-ucMGP). Total vitamin K intake was below the recommended level in 50% of patients. Lower vitamin K intake was associated with less consumption of green vegetables (33 vs 40 g/d, p?=?0.06) and increased dp-ucMGP levels (621 vs 852 pmol/L, p<0.05). Accordingly, dp-ucMGP levels were elevated (>500 pmol/L) in 80% of patients. Multivariate regression identified creatinine clearance, coumarin use, body mass index, high sensitivity-CRP and sodium excretion as independent determinants of dp-ucMGP levels. In a considerable part of the kidney transplant population, vitamin K intake is too low for maximal carboxylation of vascular MGP. The high dp-ucMGP levels may result in an increased risk for arterial calcification. Whether increasing vitamin K intake may have health benefits for kidney transplant recipients should be addressed by future studies.
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Project description:IntroductionTo explore the association between serum Dephosphorylated uncarboxylated matrix Gla protein (dp-ucMGP) and abdominal aortic calcification (AAC) in peritoneal dialysis (PD) patients.MethodsA total 128 PD patients and 120 healthy controls were enrolled into the study. Serum dp-ucMGP was measured by enzyme-linked immunosorbent assay. Abdominal lateral plain radiography was used to evaluate the abdominal aortic calcification score (AACS). PD patients were divided into two groups according to the presence or absence of AAC. The relationships between dp-ucMGP levels and AACS were assessed by Spearman analysis and the value of dp-ucMGP in predicting AAC was evaluated by receiver operating characteristic (ROC).ResultsSerum dp-ucMGP in PD patients were significantly higher than controls (p < 0.05). And PD patients with AAC had higher serum dp-ucMGP than that of PD patients without AAC (p < 0.05). The serum dp-ucMGP levels was positively associated with AACS (r = 0.794, p < 0.0001) in PD patients. The multivariate logistic regression analyses showed that serum dp-ucMGP was independent factors of AAC in PD patients (OR = 2.555, 95% CI = 1.415-4.609). The area under ROC curve of dp-ucMGP was 0.9227, the corresponding sensitivity was 0.86, and the specificity was 0.92.ConclusionSerum dp-ucMGP levels were positively associated with the AACS in PD patients. Higher serum dp-ucMGP level is independently associated with AAC in PD patients.
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Project description:Matrix Gla protein (Mgp) and bone Gla protein (Bgp) are vitamin-K dependent proteins that bind calcium in their γ-carboxylated versions in mammals. They are recognized as positive (Bgp) or negative (Mgp and Bgp) regulators of biomineralization in a number of tissues, including skeletal tissues of bony vertebrates. The Mgp/Bgp gene family is poorly known in cartilaginous fishes, which precludes the understanding of the evolution of the biomineralization toolkit at the emergence of jawed vertebrates. Here we took advantage of recently released genomic and transcriptomic data in cartilaginous fishes and described the genomic loci and gene expression patterns of the Mgp/Bgp gene family. We identified three genes, Mgp1, Mgp2, and Bgp, in cartilaginous fishes instead of the single previously reported Mgp gene. We describe their genomic loci, resulting in a dynamic evolutionary scenario for this gene family including several events of local (tandem) duplications, but also of translocation events, along jawed vertebrate evolution. We describe the expression patterns of Mgp1, Mgp2, and Bgp in embryonic stages covering organogenesis in the small-spotted catshark Scyliorhinus canicula and present a comparative analysis with Mgp/Bgp family members previously described in bony vertebrates, highlighting ancestral features such as early embryonic, soft tissues, and neuronal expressions, but also derived features of cartilaginous fishes such as expression in fin supporting fibers. Our results support an ancestral function of Mgp in skeletal mineralization and a later derived function of Bgp in skeletal development that may be related to the divergence of bony vertebrates.
| S-EPMC8006282 | biostudies-literature
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