OSTEOPONTIN, AN INDUCIBLE INHIBITOR OF VASCULAR CALCIFICATION IN MATRIX GLA PROTEIN-DEFICIENT MICE

2002 ◽  
Author(s):  
Mei Y. Speer ◽  
Marc D. McKee ◽  
Robert E. Guldberg ◽  
Lucy Liaw ◽  
Gerard Karsenty ◽  
...  
Keyword(s):  
Vascular Calcification ◽  
Matrix Gla Protein ◽  
Deficient Mice

scholarly journals Circulating Levels of Dephosphorylated-Uncarboxylated Matrix Gla Protein in Patients with Acute Coronary Syndrome

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 1108
Author(s):  
Admira Bilalic ◽  
Tina Ticinovic Kurir ◽  
Marko Kumric ◽  
Josip A. Borovac ◽  
Andrija Matetic ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Coronary Syndrome ◽  
High Risk ◽  
Hospital Mortality ◽  
Vascular Calcification ◽  
Matrix Gla Protein ◽  
St Elevation Myocardial Infarction ◽  
Coronary Syndrome ◽  
Increased Risk ◽  
St Elevation

Vascular calcification contributes to the pathogenesis of coronary artery disease while matrix Gla protein (MGP) was recently identified as a potent inhibitor of vascular calcification. MGP fractions, such as dephosphorylated-uncarboxylated MGP (dp-ucMGP), lack post-translational modifications and are less efficient in vascular calcification inhibition. We sought to compare dp-ucMGP levels between patients with acute coronary syndrome (ACS), stratified by ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI) status. Physical examination and clinical data, along with plasma dp-ucMGP levels, were obtained from 90 consecutive ACS patients. We observed that levels of dp-ucMGP were significantly higher in patients with NSTEMI compared to STEMI patients (1063.4 ± 518.6 vs. 742.7 ± 166.6 pmol/L, p < 0.001). NSTEMI status and positive family history of cardiovascular diseases were only independent predictors of the highest tertile of dp-ucMGP levels. Among those with NSTEMI, patients at a high risk of in-hospital mortality (adjudicated by GRACE score) had significantly higher levels of dp-ucMGP compared to non-high-risk patients (1417.8 ± 956.8 vs. 984.6 ± 335.0 pmol/L, p = 0.030). Altogether, our findings suggest that higher dp-ucMGP levels likely reflect higher calcification burden in ACS patients and might aid in the identification of NSTEMI patients at increased risk of in-hospital mortality. Furthermore, observed dp-ucMGP levels might reflect differences in atherosclerotic plaque pathobiology between patients with STEMI and NSTEMI.

scholarly journals Role of Matrix Gla Protein in the Complex Network of Coronary Artery Disease: A Comprehensive Review

Life ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 737
Author(s):  
Marko Kumric ◽  
Josip A. Borovac ◽  
Tina Ticinovic Kurir ◽  
Dinko Martinovic ◽  
Ivan Frka Separovic ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Complex Network ◽  
Vascular Calcification ◽  
Vitamin K ◽  
Clinical Decision Making ◽  
Large Body ◽  
Matrix Gla Protein ◽  
Artery Disease

Coronary artery disease (CAD) is widely recognized as one of the most important clinical entities. In recent years, a large body of accumulated data suggest that coronary artery calcification, a process highly prevalent in patients with CAD, occurs via well-organized biologic processes, rather than passively, as previously regarded. Matrix Gla protein (MGP), a vitamin K-dependent protein, emerged as an important inhibitor of both intimal and medial vascular calcification. The functionality of MGP hinges on two post-translational modifications: phosphorylation and carboxylation. Depending on the above-noted modifications, various species of MGP may exist in circulation, each with their respective level of functionality. Emerging data suggest that dysfunctional species of MGP, markedly, dephosphorylated-uncarboxylated MGP, might find its application as biomarkers of microvascular health, and assist in clinical decision making with regard to initiation of vitamin K supplementation. Hence, in this review we summarized the current knowledge with respect to the role of MGP in the complex network of vascular calcification with concurrent inferences to CAD. In addition, we discussed the effects of warfarin use on MGP functionality, with concomitant implications to coronary plaque stability.

Abstract 17763: Inhibition of Bone Morphogenetic Protein Signaling Reduces Endothelial-Mesenchymal Transition and Vascular Smooth Muscle Cell Calcification Associated with Matrix Gla Protein Deficiency

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Megan F Burke ◽  
Caitlin O’Rourke ◽  
Trejeeve Martyn ◽  
Hannah R Shakartzi ◽  
Timothy E Thayer ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Bone Morphogenetic Protein ◽  
Vascular Calcification ◽  
Bmp Signaling ◽  
Matrix Gla Protein ◽  
Wild Type ◽  
Mesenchymal Transition ◽  
Morphogenetic Protein ◽  
Endothelial Mesenchymal Transition

Background: Matrix Gla protein (MGP) is an extracellular matrix protein that inhibits bone morphogenetic protein (BMP) signaling in vitro. MGP deficiency induces vascular calcification associated with osteogenic transdifferentiation of endothelial cells (via endothelial-mesenchymal transition, EndMT) and vascular smooth muscle cells (VSMCs). We previously reported that treatment with two pharmacologic inhibitors of BMP signaling reduced aortic calcification in MGP-/- mice. We hypothesized that BMP signaling is essential for EndMT and VSMC osteogenic transdifferentiation induced by MGP deficiency. Methods and Results: Aortic levels of mRNAs encoding markers of osteogenesis (Runx2 and osteopontin) and EndMT (nanog, Sox2, and Oct3/4) were greater in MGP-/- than in wild-type mice (P<0.01 for all). Aortic expression of markers of VSMC differentiation (α-smooth muscle actin, transgelin, and calponin) was less in MGP-/- than in wild-type mice (P<0.001 for all). Treatment of MGP-/- mice with the BMP signaling inhibitor, LDN-193189, reduced expression of both osteogenic and EndMT markers (P<0.05 for all) but did not prevent VSMC de-differentiation. Depletion of MGP in cultured wild-type VSMCs with siRNA specific for MGP (siMGP) was associated with a 30-40% reduction in levels of mRNAs encoding markers of VSMC differentiation (P<0.05 for all), an effect that was not prevented by LDN-193189. Incubation in phosphate-containing media induced greater calcification in siMGP-treated VSMCs than in cells treated with control siRNA (P<0.0001). Treatment with LDN-193189 reduced calcification in siMGP-treated VSMCs (50%, P=0.0003). Conversely, infection of MGP-/- VSMCs with adenovirus specifying MGP increased expression of markers of VSMC differentiation by 60-80% (P<0.01 for all) and decreased calcification by 74% (P=0.03). Conclusions: Inhibition of BMP signaling suppresses osteogenic and EndMT gene programs in MGP-/- mice and reduces calcification of siMGP-treated VSMCs. However, MGP deficiency induces VSMC de-differentiation via a BMP-independent mechanism. These findings suggest that the processes underlying vascular calcification in MGP deficiency are mediated by both BMP signaling-dependent and -independent mechanisms.

P1645VITAMIN K DEPENDENT PROTEINS AFTER KIDNEY TRANSPLANTATION: RESULTS FROM PROSPECTIVE STUDY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Maria Fusaro ◽  
Pascale Khairallah ◽  
Andrea Aghi ◽  
Mario Plebani ◽  
Martina Zaninotto ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Prospective Study ◽  
Vascular Calcification ◽  
Vitamin K ◽  
Matrix Gla Protein ◽  
Bone Gla Protein ◽  
Vitamin K Deficiency ◽  
Prospective Data ◽  
K Deficiency ◽  
The Impact

Abstract Background and Aims Two Vitamin K-dependent proteins (VDKPs) link bone and vasculature in CKD-MBD: Bone Gla Protein (BGP) and Matrix Gla Protein (MGP). In ESKD, Vitamin K deficiency is highly prevalent and leads to increased levels of inactive VKDPs (undercaboxylated (ucBGP and dephosphorylated (dp)-uMGP), which are linked to greater risk of fractures and severity of vascular calcification. We hypothesized that kidney transplantation (KT) would improve Vitamin K status and lower levels of inactive VKDPs. Method Between 2014-2017, we conducted a study in 34 patients to assess changes in VKDPs during the 1st year of KT. In a specialized lab we determined VKDPs pre- and 1-year post-KT: total BGP, uc BGP, total MGP, and dp-uc MGP. We determined the prevalence of Vitamin K deficiency based on levels of uc BGP and dp-uc MGP. Results Our cohort had a mean +/- SD age of 48+/-14 years, 32% were female and 97% were Caucasian. 1 year post-KT, there was a decrease in the levels of all VKDPs and the prevalence of Vitamin K deficiency (Table 1 and Figure 1). Patients with greatest severity of Vitamin K deficiency pre-KT had the largest decreases of inactive VDKPs post-KT. Conclusion KT was associated with improvement in Vitamin K status as manifested by decreased levels of inactive VKDPs. These are the first prospective data on VKDPs in CKD patients pre- and post-KT. Studies are needed to assess the impact of improvement in VKDP status after KT on CKD-MBD outcomes.

P0791MATRIX GLA PROTEIN AND PREMATURE VASCULAR CALCIFICATION IN PATIENTS WITH END-STAGE RENAL DISEASE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Lu Dai ◽  
Abdul Rashid Tony Qureshi ◽  
Jonaz Ripsweden ◽  
Torkel B Brismar ◽  
Magnus Söderberg ◽  
...  
Keyword(s):  
Renal Disease ◽  
Vascular Calcification ◽  
Vitamin K ◽  
End Stage Renal Disease ◽  
Protective Factor ◽  
Matrix Gla Protein ◽  
Vascular Aging ◽  
Dialysis Vintage ◽  
Stage Renal Disease ◽  
End Stage

Abstract Background and Aims Vitamin K is a potential protective factor against premature vascular aging and vascular calcification (VC). Whether vitamin K supplement could halt VC progression in patients with end-stage renal disease (ESRD) is not clear, partially due to the heterogeneity of measurements of VC in different vascular sites. Here we investigated the associations between non-phosphorylated, uncarboxylated matrix-Gla protein (dp-ucMGP), a circulating marker of vitamin K insufficiency, and premature vascular aging phenotypes evaluated by coronary artery calcium (CAC) scoring, aortic valve calcium (AVC) scoring, and histology scoring of presence of media calcification in vascular biopsies in patients with ESRD. Method In this observational cohort study, 223 ESRD patients (median age 54 years, 68% males) comprising non-dialysis patients (n=109), prevalent peritoneal dialysis (PD, n=80, median dialysis vintage 11.6 months) and prevalent hemodialysis patients (HD, n=34, median dialysis vintage 12.0 months) underwent baseline measurements of plasma dp-ucMGP and scoring of CAC and AVC by computed tomography scan. Framingham risk score (FRS), inflammation and other relevant clinical and biochemical data were determined at baseline. In a sub-group of patients (n=94), scoring of media calcification by histology in epigastric artery biopsies was also performed. Results Plasma dp-ucMGP levels (median 1568 pmol/L) significantly correlated with age (rho=0.38), presence of cardiovascular disease (CVD, rho=0.16), triglycerides (rho=0.19), FRS (rho=0.33), high-sensitivity C-reactive protein (hsCRP; rho=0.35), CAC score (rho=0.30) and AVC score (rho=0.24) but did not differ with regards to treatment modality (i.e. non-dialysis, PD and HD). In multivariate regression analyses, with adjustment for presence of CVD, FRS, hsCRP and triglycerides, increased dp-ucMGP levels were independently associated with increased CAC score (coefficients 0.12, p=0.04), but not with AVC score nor presence of media calcification in epigastric arteries. Conclusion Our data suggest that vitamin K insufficiency as indicated by increased dp-ucMGP levels associates with premature vascular calcification evaluated by CAC but not with AVC or media calcification assessed by histology. This discrepancy warrants further studies to explore the pathophysiological background between vitamin K metabolism and susceptibility of calcification in different vascular sites as well as the pattern of VC (i.e. intima and media calcification) within sites.

scholarly journals Emerging Role of Vitamins D and K in Modulating Uremic Vascular Calcification: The Aspect of Passive Calcification

Nutrients ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 152 ◽  
Author(s):  
Yi-Chou Hou ◽  
Chien-Lin Lu ◽  
Cai-Mei Zheng ◽  
Ruei-Ming Chen ◽  
Yuh-Feng Lin ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Vitamin D ◽  
Kidney Disease ◽  
Vascular Calcification ◽  
Vitamin K ◽  
Matrix Vesicles ◽  
Vital Role ◽  
Matrix Gla Protein ◽  
Protein Receptor ◽  
Calciprotein Particles

Vascular calcification is a critical complication in patients with chronic kidney disease (CKD) because it is predictive of cardiovascular events and mortality. In addition to the traditional mechanisms associated with endothelial dysfunction and the osteoblastic transformation of vascular smooth muscle cells (VSMCs), the regulation of calcification inhibitors, such as calciprotein particles (CPPs) and matrix vesicles plays a vital role in uremic vascular calcification in CKD patients because of the high prevalence of vitamin K deficiency. Vitamin K governs the gamma-carboxylation of matrix Gla protein (MGP) for inhibiting vascular calcification, and the vitamin D binding protein receptor is related to vitamin K gene expression. For patients with chronic kidney disease, adequate use of vitamin D supplements may play a role in vascular calcification through modulation of the calciprotein particles and matrix vesicles (MVs).

An Overview of the Pathophysiology of Vascular Calcification in Chronic Kidney Disease

2007 ◽  
Vol 27 (2_suppl) ◽  
pp. 215-222 ◽  
Author(s):  
Tomasz Stompór
Keyword(s):  
Chronic Kidney Disease ◽  
Calcium Phosphate ◽  
Kidney Disease ◽  
Vascular Calcification ◽  
Vessel Wall ◽  
Matrix Gla Protein ◽  
Soft Tissue Calcification ◽  
Poor Control ◽  
Bone Morphogenetic Protein 7 ◽  
Morphogenetic Protein

Abnormalities of calcium–phosphate balance, with subsequent bone metabolism disorders, are among the key and earliest features of chronic kidney disease (CKD). Recently, another consequence of these abnormalities was brought to light—namely, vascular calcification. Most studies performed in patients on dialysis suggest that their vascular calcification is more advanced than that seen in the general population. Furthermore, the progression of vessel wall mineralization is much more dynamic in patients with CKD. Apart from the commonly assessed factors that promote vascular calcification, such as age, duration of dialysis, or poor control of calcium–phosphate status, several other factors have recently been identified. In the spectrum of substances involved in the regulation of the process of soft-tissue calcification, the most extensively studied in the nephrology literature are bone morphogenetic protein 7, osteoprotegerin, matrix Gla protein, fetuin-A, and the phosphatonins. Better understanding of the mechanisms underlying excess vascular mineralization have led to the development of promising new therapies.

scholarly journals Effect of Leptin on Vascular Calcification in Apolipoprotein E–Deficient Mice

2009 ◽  
Vol 29 (12) ◽  
pp. 2069-2075 ◽  
Author(s):  
Melec Zeadin ◽  
Martin Butcher ◽  
Geoff Werstuck ◽  
Mohammad Khan ◽  
Colin K. Yee ◽  
...  
Keyword(s):  
Apolipoprotein E ◽  
Vascular Calcification ◽  
Deficient Mice
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