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      High-Dose Menaquinone-7 Supplementation Reduces Cardiovascular Calcification in a Murine Model of Extraosseous Calcification

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          Abstract

          Cardiovascular calcification is prevalent in the aging population and in patients with chronic kidney disease (CKD) and diabetes mellitus, giving rise to substantial morbidity and mortality. Vitamin K-dependent matrix Gla-protein (MGP) is an important inhibitor of calcification. The aim of this study was to evaluate the impact of high-dose menaquinone-7 (MK-7) supplementation (100 µg/g diet) on the development of extraosseous calcification in a murine model. Calcification was induced by 5/6 nephrectomy combined with high phosphate diet in rats. Sham operated animals served as controls. Animals received high or low MK-7 diets for 12 weeks. We assessed vital parameters, serum chemistry, creatinine clearance, and cardiac function. CKD provoked increased aortic (1.3 fold; p < 0.05) and myocardial (2.4 fold; p < 0.05) calcification in line with increased alkaline phosphatase levels (2.2 fold; p < 0.01). MK-7 supplementation inhibited cardiovascular calcification and decreased aortic alkaline phosphatase tissue concentrations. Furthermore, MK-7 supplementation increased aortic MGP messenger ribonucleic acid (mRNA) expression (10-fold; p < 0.05). CKD-induced arterial hypertension with secondary myocardial hypertrophy and increased elastic fiber breaking points in the arterial tunica media did not change with MK-7 supplementation. Our results show that high-dose MK-7 supplementation inhibits the development of cardiovascular calcification. The protective effect of MK-7 may be related to the inhibition of secondary mineralization of damaged vascular structures.

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          Most cited references48

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          K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification.

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            Vascular calcification: an update on mechanisms and challenges in treatment.

            Vascular calcification is highly associated with cardiovascular disease mortality, particularly in high-risk patients with diabetes and chronic kidney diseases (CKD). In blood vessels, intimal calcification is associated with atherosclerosis, whereas medial calcification is a nonocclusive process which leads to increased vascular stiffness and reduced vascular compliance. In the valves, calcification of the leaflets can change the mechanical properties of the tissue and result in stenosis. For many decades, vascular calcification has been noted as a consequence of aging. Studies now confirm that vascular calcification is an actively regulated process and shares many features with bone development and metabolism. This review provides an update on the mechanisms of vascular calcification including the emerging roles of the RANK/RANKL/OPG triad, osteoclasts, and microRNAs. Potential treatments adapted from osteoporosis and CKD treatments that are under investigation for preventing and/or regressing vascular calcification are also reviewed.
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              Vitamin K-dependent carboxylation of matrix Gla-protein: a crucial switch to control ectopic mineralization.

              Vascular mineralization has recently emerged as a risk factor for cardiovascular morbidity and mortality. Previously regarded as a passive end-stage process, vascular mineralization is currently recognized as an actively regulated process with cellular and humoral contributions. The discovery that the vitamin K-dependent matrix Gla-protein (MGP) is a strong inhibitor of vascular calcification has propelled our mechanistic understanding of this process and opened novel avenues for diagnosis and treatment. This review focuses on molecular mechanisms of vascular mineralization involving MGP and discusses the potential for treatments and biomarkers to monitor patients at risk for vascular mineralization. Copyright © 2013 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Nutrients
                Nutrients
                nutrients
                Nutrients
                MDPI
                2072-6643
                18 August 2015
                August 2015
                : 7
                : 8
                : 6991-7011
                Affiliations
                [1 ]Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, University Duesseldorf, Duesseldorf 40225, Germany; E-Mails: daniel.scheiber@ 123456med.uni-duesseldorf.de (D.S.); verena.veulemanns@ 123456med.uni-duesseldorf.de (V.V.); patrick.horn@ 123456med.uni-duesseldorf.de (P.H.); malte.kelm@ 123456med.uni-duesseldorf.de (M.K.)
                [2 ]Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht 6229 ER, The Netherlands; E-Mails: m.chatrou@ 123456maastrichtuniversity.nl (M.L.C.); l.schurgers@ 123456maastrichtuniversity.nl (L.J.S.)
                [3 ]Department of Nephrology, University Duesseldorf, Medical Faculty, Duesseldorf 40225, Germany; E-Mail: sebastian.potthoff@ 123456med.uni-duesseldorf.de
                [4 ]Cardiovascular Research Institute Duesseldorf, University Duesseldorf, Medical Faculty, Duesseldorf 40225, Germany
                Author notes
                [†]

                These authors contributed equally to this work.

                [* ]Author to whom correspondence should be addressed; E-Mail: ralf.westenfeld@ 123456med.uni-duesseldorf.de ; Tel.: +49-211-8118800; Fax: +49-211-8118812.
                Article
                nutrients-07-05318
                10.3390/nu7085318
                4555157
                26295257
                803f511e-13d0-48ba-b6e3-dd2c2b2807b3
                © 2015 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 license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 15 May 2015
                : 06 August 2015
                Categories
                Article

                Nutrition & Dietetics
                menaquinone-7,vitamin k2,cardiovascular calcification,matrix gla-protein,chronic kidney disease

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