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      Association of the Inactive Circulating Matrix Gla Protein with Vitamin K Intake, Calcification, Mortality, and Cardiovascular Disease: A Review

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          Abstract

          Matrix Gla Protein (MGP), a small Gla vitamin K-dependent protein, is the most powerful natural occurring inhibitor of calcification in the human body. To become biologically active, MGP must undergo vitamin K-dependent carboxylation and phosphorylation. Vitamin K deficiency leads to the inactive uncarboxylated, dephosphorylated form of MGP (dpucMGP). We aimed to review the existing data on the association between circulating dpucMGP and vascular calcification, renal function, mortality, and cardiovascular disease in distinct populations. Moreover, the association between vitamin K supplementation and serum levels of dpucMGP was also reviewed.

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          Dialysis accelerates medial vascular calcification in part by triggering smooth muscle cell apoptosis.

          Vascular calcification is associated with increased morbidity and mortality in stage V chronic kidney disease, yet its early pathogenesis and initiating mechanisms in vivo remain poorly understood. To address this, we quantified the calcium (Ca) load in arteries from children (10 predialysis, 24 dialysis) and correlated it with clinical, biochemical, and vascular measures. Vessel Ca load was significantly elevated in both predialysis and dialysis and was correlated with the patients' mean serum Ca x phosphate product. However, only dialysis patients showed increased carotid intima-media thickness and increased aortic stiffness, and calcification on computed tomography was present in only the 2 patients with the highest Ca loads. Importantly, predialysis vessels appeared histologically intact, whereas dialysis vessels exhibited evidence of extensive vascular smooth muscle cell (VSMC) loss owing to apoptosis. Dialysis vessels also showed increased alkaline phosphatase activity and Runx2 and osterix expression, indicative of VSMC osteogenic transformation. Deposition of the vesicle membrane marker annexin VI and vesicle component mineralization inhibitors fetuin-A and matrix Gla-protein increased in dialysis vessels and preceded von Kossa positive overt calcification. Electron microscopy showed hydroxyapatite nanocrystals within vesicles released from damaged/dead VSMCs, indicative of their role in initiating calcification. Taken together, this study shows that Ca accumulation begins predialysis, but it is the induction of VSMC apoptosis in dialysis that is the key event in disabling VSMC defense mechanisms and leading to overt calcification, eventually with clinically detectable vascular damage. Thus the identification of factors that lead to VSMC death in dialysis will be of prime importance in preventing vascular calcification.
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            Prognostic value of coronary artery calcium screening in subjects with and without diabetes.

            The study was done to determine the interaction of coronary artery calcium and diabetes mellitus for prediction of all-cause death. Diabetes is a strong risk factor for coronary artery disease (CAD) and is associated with an elevated overall mortality. Electron beam tomography (EBT) provides information on the presence of subclinical atherosclerosis and may be useful for risk stratification. We followed 10,377 asymptomatic individuals (903 diabetic patients) referred for EBT imaging. Primary end point was all-cause mortality, and the average follow-up was 5.0 +/- 3.5 years. Cox proportional hazard models, with and without adjustment for other risk factors, were developed to predict all-cause mortality. Patients with diabetes had a higher prevalence of hypertension and smoking (p < 0.001) and were older. The average coronary calcium score (CCS) for subjects with and for those without diabetes was 281 +/- 567 and 119 +/- 341, respectively (p < 0.0001). Overall, the death rate was 3.5% and 2.0% for subjects with and without diabetes (p < 0.0001). In a risk-factor-adjusted model, there was a significant interaction of CCS with diabetes (p < 0.00001), indicating that, for every increase in CCS, there was a greater increase in mortality for diabetic than for nondiabetic subjects. However, patients suffering from diabetes with no coronary artery calcium demonstrated a survival similar to that of individuals without diabetes and no detectable calcium (98.8% and 99.4%, respectively, p = 0.5). Mortality from all causes is increased in asymptomatic patients with diabetes in proportion to the screening CCS. Nonetheless, subjects without coronary artery calcium have a low short-term risk of death even in the presence of diabetes mellitus.
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              Differential expression of bone matrix regulatory proteins in human atherosclerotic plaques.

              In the present study, we examined the expression of regulators of bone formation and osteoclastogenesis in human atherosclerosis because accumulating evidence suggests that atherosclerotic calcification shares features with bone calcification. The most striking finding of this study was the constitutive immunoreactivity of matrix Gla protein, osteocalcin, and bone sialoprotein in nondiseased aortas and the absence of bone morphogenetic protein (BMP)-2, BMP-4, osteopontin, and osteonectin in nondiseased aortas and early atherosclerotic lesions. When atherosclerotic plaques demonstrated calcification or bone formation, BMP-2, BMP-4, osteopontin, and osteonectin were upregulated. Interestingly, this upregulation was associated with a sustained immunoreactivity of matrix Gla protein, osteocalcin, and bone sialoprotein. The 2 modulators of osteoclastogenesis (osteoprotegerin [OPG] and its ligand, OPGL) were present in the nondiseased vessel wall and in early atherosclerotic lesions. In advanced calcified lesions, OPG was present in bone structures, whereas OPGL was only present in the extracellular matrix surrounding calcium deposits. The observed expression patterns suggest a tight regulation of the expression of bone matrix regulatory proteins during human atherogenesis. The expression pattern of both OPG and OPGL during atherogenesis might suggest a regulatory role of these proteins not only in osteoclastogenesis but also in atherosclerotic calcification.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                01 February 2019
                February 2019
                : 20
                : 3
                : 628
                Affiliations
                [1 ]Division of Nephrology and Hypertension, 1st Department of Internal Medicine, AHEPA Hospital, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; st_roumeliotis@ 123456hotmail.com (S.R.); teleftheriadis@ 123456yahoo.com (T.E.)
                [2 ]Department of Nephrology, Medical School, University of Ioannina, 45110 Ioannina, Greece; evangeldou@ 123456gmail.com
                Author notes
                [* ]Correspondence: liakopul@ 123456otenet.gr ; Tel.: +302310994694
                Author information
                https://orcid.org/0000-0001-9302-1633
                https://orcid.org/0000-0002-7564-2724
                Article
                ijms-20-00628
                10.3390/ijms20030628
                6387246
                30717170
                9b96b757-b248-4aa4-82e3-05f3b507e9ba
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 05 January 2019
                : 30 January 2019
                Categories
                Review

                Molecular biology
                calcification,cardiovascular disease,dpucmgp,matrix gla protein,mortality,renal function,vitamin k.

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