Matrix Gla protein (MGP) and bone morphogenetic protein-2 in aortic calcified lesions of aging rats

Sweatt, Andrew J.; Sane, David C.; Hutson, Susan M.; Wallin, Reidar

doi:10.1046/j.1538-7836.2003.00023.x

Cited by 150 publications

(138 citation statements)

References 20 publications

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“…This can be seen in Figures 2 and 3 in which the majority of the newly synthesized MGP is produced in the undercarboxylated, inactive form. This is in agreement with work from Sweatt et al 13 who showed that in aging rats ucMGP was associated with arterial calcification as demonstrated with polyclonal conformation-specific MGP antibodies. The researchers concluded that inactive MGP because of vitamin K deficiency could lead to arterial calcifications.…”

Section: Discussionsupporting

confidence: 93%

“…MGP acts by direct inhibition of calcium crystal formation and regulates bone morphogenetic protein-2, a growth factor responsible for osteogenic differentiation. [11][12][13] Murshed et al 14 demonstrated that restoration of MGP exclusively in the vascular smooth muscle cells of the MGP-null mice completely rescued the vascular calcification phenotype. For this effect the MGP needed to be ␥-carboxylated because mutating the Gla residues into aspartic acid residues led to the synthesis of nonfunctional MGP and to the death of all animals.…”

Section: Introductionmentioning

confidence: 99%

“…26,27 Further studies using immunohistochemical analysis with conformation-specific antibodies demonstrated that in calcifying carotid arteries MGP predominantly occurs in the noncarboxylated form, suggesting that the local vitamin K status is suboptimal. 13,28 The rat arterial calcification model, as developed by Price et al 20 and used by others, 21,25,29 has thus far only looked at the development of arterial calcification. The aim of the present study was to use the rat arterial calcification model to investigate whether maximal MGP activity, ascertained by high-vitamin K intake, may stop the progression or even induce a reversal of warfarin-induced arterial calcification and the associated decrease in arterial distensibility.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats

Schurgers

Spronk

Soute

et al. 2006

Blood

230

204

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Arterial calcification (AC) is generally regarded as an independent risk factor for cardiovascular morbidity and mortality. Matrix Gla protein (MGP) is a potent inhibitor of AC, and its activity depends on vitamin K (VK). In rats, inactivation of MGP by treatment with the vitamin K antagonist warfarin leads to rapid calcification of the arteries. Here, we investigated whether preformed AC can be regressed by a VK-rich diet. Rats received a calcification-inducing diet containing both VK and warfarin (W&K). During a second 6-week period, animals were randomly assigned to receive either W&K (3.0 mg/g and 1.5 mg/g, subsequently), a diet containing a normal (5 g/g) or high (100 g/g) amount of VK (either K 1 or K 2 ). Increased aortic calcium concentration was observed in the group that continued to receive W&K and also in the group changed to the normal dose of VK and AC progressed. Both the VK-rich diets decreased the arterial calcium content by some 50%. In addition, arterial distensibility was restored by the VK-rich diet. Using MGP antibodies, local VK deficiency was demonstrated at sites of calcification. This is the first study in rats demonstrating that AC and the resulting decreased arterial distensibility are reversible by high-VK intake. IntroductionArterial calcification is an important independent risk factor for the development of atherosclerosis, myocardial infarction, stroke, and renal disease. 1,2 Patients with manifest arterial calcification have an unfavorable prognosis compared with patients with no or mild calcification. 3,4 Therefore, the prevention or reversal of arterial calcification may lead to improved patient outcomes.For a long time it has been thought that calcification was a passive process and the end stage of cardiovascular disease. During the past 10 years, however, it has become clear that several osteoregulatory proteins, both stimulatory and inhibitory, are involved in the calcification of vascular tissue. [5][6][7][8] One of the strongest in vivo inhibitors of arterial calcification is matrix Gla protein (MGP). MGP was first discovered in bone, 9 but it is mainly produced by vascular smooth muscle cells and chondrocytes. Its function became clear in MGP-deficient mice, 10 which died within 6 to 8 weeks after birth as a result of rupture of the large arteries. Histochemical evaluation demonstrated complete calcification of the elastic fibers in the arterial vessels and a phenotypic change of smooth muscle cells into chondrocytes. MGP acts by direct inhibition of calcium crystal formation and regulates bone morphogenetic protein-2, a growth factor responsible for osteogenic differentiation. [11][12][13] Murshed et al 14 demonstrated that restoration of MGP exclusively in the vascular smooth muscle cells of the MGP-null mice completely rescued the vascular calcification phenotype. For this effect the MGP needed to be ␥-carboxylated because mutating the Gla residues into aspartic acid residues led to the synthesis of nonfunctional MGP and to the death of all animals.Vitamin K is an e...

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats

Schurgers

Spronk

Soute

et al. 2006

Blood

230

204

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“…These data support the hypothesis that the Gla region in MGP indeed is involved in BMP-2 binding and regulation of the ostergenic growth factor activity of BMP-2. The data also add support to our earlier finding that overexpression of non γ-carboxylated MGP in calcified lesions in the aorta of aging rats results in unopposed BMP-2 activity which may contribute to osteoblastic differenation of cells laying down the observed calcified matrix (29). BMP-2 at 5 nM was used in all experiments and significantly higher concentrations of the Gla-and the Glu-MGP peptides were needed to measure significant inhibitory effects.…”

Section: Discussionsupporting

confidence: 84%

Effects of the blood coagulation vitamin K as an inhibitor of arterial calcification

Wallin

Schurgers

Wajih

2008

Thrombosis Research

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Introduction-The transformation of smooth muscle cells (VSMCs) in the vessel wall to osteoblast like cells is known to precede arterial calcification which may cause bleeding complications. The vitamin K-dependent protein MGP has been identified as an inhibitor of this process by binding BMP-2, a growth factor known to trigger the transformation. In this study, we determined if the vitamin K-dependent Gla region in MGP by itself can inhibit the growth factor activity of BMP-2 and if menaquinone-4 (MK4) regulates gene expression in VSMCs.

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“…tein-protein interaction between BMP-2 and MGP (20,53,54) and modulation of BMP-2 activity (19 -21). Alternatively, it may target specific ligand-receptor complexes analogous to endoglin (55) or betaglycan (56), or it may alter the balance between signaling through the canonical Smad pathway and other, non-canonical signaling pathways (25).…”

Section: Figmentioning

confidence: 99%

Matrix GLA Protein Stimulates VEGF Expression through Increased Transforming Growth Factor-β1 Activity in Endothelial Cells

Boström

Zebboudj

Yao

et al. 2004

Journal of Biological Chemistry

105

120

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Matrix Gla protein (MGP) and bone morphogenetic protein-2 in aortic calcified lesions of aging rats

Cited by 150 publications

References 20 publications

Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats

Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats

Effects of the blood coagulation vitamin K as an inhibitor of arterial calcification

Matrix GLA Protein Stimulates VEGF Expression through Increased Transforming Growth Factor-β1 Activity in Endothelial Cells

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