Inactive Matrix Gla Protein Is Causally Related to Adverse Health Outcomes

Liu, Yan Ping; Gu, Yuxuan; Thijs, Lutgarde; Knapen, Marjo H. J.; Citterio, Lorena; Petit, Thibault; Carpini, Simona Delli; Zhang, Zhenyu; Jacobs, Lotte; Jin, Yu; Barlassina, Cristina; Manunta, Paolo; Kuznetsova, Tatiana; Verhamme, Peter; Struijker‐Boudier, Harry A.J.; Cusi, Daniele; Vermeer, Cees; Staessen, Jan A.

doi:10.1161/hypertensionaha.114.04494

Cited by 83 publications

(94 citation statements)

References 46 publications

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“…Finally, a recent Mendelian randomization study found that higher dp-ucMGP predicts noncancer mortality. 31 The Mendelian design strongly supports a causal relationship and also favors the hypothesis that dp-ucMGP is not solely a biomarker of vascular vitamin K status, although both hypotheses could be true.…”

Section: Discussionmentioning

confidence: 71%

Inactive Matrix Gla-Protein Is Associated With Arterial Stiffness in an Adult Population–Based Study

et al. 2015

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Increased pulse wave velocity (PWV) is the gold standard in assessing stiffening of the aorta.1 As shown by 3 population studies, all including over thousand participants, PWV refines risk stratification above and beyond traditional cardiovascular risk factors. In multivariable-adjusted analyses, per one standard deviation (SD) increment in PWV, cardiovascular mortality increased by 20% and 60% in a Danish and Taiwanese population samples, respectively.2,3 The Framingham heart study found that one standard deviation increment of PWV was associated with a 48% increase in cardiovascular disease risk. 4 Matrix Gla-protein (MGP) is acting as a strong inhibitor of soft tissue calcification. 5,6 MGP knockout mice develop massive vascular calcification in their first weeks of life and die within 2 months of vessels rupture.7 MGP is expressed primarily by chondrocytes and vascular smooth muscle cells. 8,9 To acquire its full calcification inhibitory activity, MGP needs to undergo 2 post-translational modifications: glutamate carboxylation and serine phosphorylation. Both modifications are not exerted completely, so theoretically, 4 different MGP conformations can be found: unmodified and Abstract-Increased pulse wave velocity (PWV) is a marker of aortic stiffness and an independent predictor of mortality.Matrix Gla-protein (MGP) is a vascular calcification inhibitor that needs vitamin K to be activated. Inactive MGP, known as desphospho-uncarboxylated MGP (dp-ucMGP), can be measured in plasma and has been associated with various cardiovascular markers, cardiovascular outcomes, and mortality. In this study, we hypothesized that high levels of dp-ucMGP are associated with increased PWV. We recruited participants via a multicenter family-based crosssectional study in Switzerland. Dp-ucMGP was quantified in plasma by sandwich ELISA. Aortic PWV was determined by applanation tonometry using carotid and femoral pulse waveforms. Multiple regression analysis was performed to estimate associations between PWV and dp-ucMGP adjusting for age, renal function, and other cardiovascular risk factors. We included 1001 participants in our analyses (475 men and 526 women). Mean values were 7.87±2.10 m/s for PWV and 0.43±0.20 nmol/L for dp-ucMGP. PWV was positively associated with dp-ucMGP both before and after adjustment for sex, age, body mass index, height, systolic and diastolic blood pressure (BP), heart rate, renal function, low-and high-density lipoprotein, glucose, smoking status, diabetes mellitus, BP and cholesterol lowering drugs, and history of cardiovascular disease (P≤0.01). In conclusion, high levels of dp-ucMGP are independently and positively associated with arterial stiffness after adjustment for common cardiovascular risk factors, renal function, and age. inactive as desphospho-uncarboxylated MGP (dp-ucMGP), only phosphorylated, only carboxylated, and finally fully modified and active as phosphorylated and carboxylated MGP. 10,11 Carboxylation of MGP is a vitamin K-dependent process: vitamin K hydroquinone, a vitamin K m...

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Section: Discussionmentioning

confidence: 71%

Inactive Matrix Gla-Protein Is Associated With Arterial Stiffness in an Adult Population–Based Study

et al. 2015

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“…High levels of plasma dp-ucMGP are a proxy for vitamin K deficiency [3,21]. Levels ranging from ∼1.4 to ∼4.6 μg/l are probably optimal in terms of the risk of mortality and macrovascular cardiovascular complications [9]. In white Flemish people, a 4.6 μg/l threshold corresponded with the 65th percentile of the dp-ucMGP distribution, indicating that 35% of the general population in Belgium might be vitamin K deficient.…”

Section: Discussionmentioning

confidence: 99%

“…In patients with diabetes [6], renal dysfunction [7], or macrovascular disease [8], inactive dp-ucMGP behaves as a circulating biomarker associated with cardiovascular risk [6], more severe illness [7], or higher mortality [8]. In the Flemish Study on Environment, Genes and Health Outcomes (FLEMENGHO), circulating dp-ucMGP predicted total and cardiovascular mortality [9]. More recently, we assessed the association of renal microvascular function as exemplified by the estimated glomerular filtration rate (eGFR) with both circulating dp-ucMGP and t-ucMGP in a multiethnic population study [10].…”

Section: Introductionmentioning

confidence: 99%

Vitamin-K-Dependent Protection of the Renal Microvasculature: Histopathological Studies in Normal and Diseased Kidneys

Wei

Drummen

Thijs

et al. 2016

Pulse

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Vitamin-K-dependent carboxylation of matrix Gla protein (MGP) protects the macrocirculation against calcification. We recently reported in a multiethnic population study that the estimated glomerular filtration rate, a microvascular trait, decreased and the risk of chronic kidney disease increased with higher circulating levels of inactive dephospho-uncarboxylated MGP, a marker of vitamin K deficiency. These findings highlighted the possibility that vitamin K might have a beneficial effect on the renal microcirculation. To substantiate these epidemiological findings, we undertook a pilot study, in which we stained renal tissue samples obtained by biopsy from 2 healthy kidney donors and 4 patients with nephropathy for carboxylated and uncarboxylated MGP and calcium deposits. Three patients had renal calcifications, which were consistently associated with carboxylated and uncarboxylated MGP. Normal renal tissue was devoid of microcalcifications and staining for carboxylated and uncarboxylated MGP. Pending confirmation in a larger study covering a wider range of renal pathologies, these histopathological findings suggest that MGP might inhibit calcification not only in large arteries, as was known before, but in renal tissue as well, thereby highlighting potentially new avenues for promoting renal health, for instance by vitamin K supplementation.

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“…Likewise, lower levels of dp-cMGP were associated with a higher calcification score and all-cause and CV mortality in CKD 47 . Both dp-ucMGP and dp-cMGP were higher in symptomatic aortic stenosis and heart failure patients 44 and among patients who had suffered a CV event, those in the highest quartile of dp-ucMGP and dpcMGP had a higher risk of all-cause and CV mortality after five years 48 . Although it had been thought that MGP and OC had their distinct spheres of effect (arteries and bone respectively) 49 , a recent study showed that in older Caucasian men higher baseline total OC (carboxylation status not assessed) predicted 10 year progression of abdominal aortic calcification and lower mortality rate 50 , while MGP appears also to be implicated in bone and cartilage formation 51 .…”

Section: Calcificationmentioning

confidence: 91%

Cardiovascular Calcification and Bone: A Comparison of the Effects of Dietary and Serum Vitamin K and its Dependent Proteins

Nicoll¹,

Howard²,

Henein³

2015

ICFJ

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This review compares the effect of vitamin K on cardiovascular (CV) calcification and bone health and shows that, in principal, the γ-carboxylation of the vitamin K-dependent proteins matrix Gla protein (MGP) and its bone equivalent osteocalcin (OC), generally ensures that hydroxyapatite is kept out of the CV system and is deposited in bone. This is an important finding, since there is currently no reliable treatment for CV calcification.Vitamin K2 (menaquinone) may be more effective in the arteries, while vitamin K1 (phylloquinone) is more active in bone. Nevertheless, there remains considerable uncertainty over the precise scope of the functions of MGP and OC, and their carboxylated and under-carboxylated forms, as well as the newly discovered vitamin K-dependent proteins. Although a diet high in vegetables could deliver adequate phylloquinone, supplementation of menaquinone may be necessary for those at risk of CV calcification. Several animal studies and one human study have demonstrated that arterial calcification could be reduced with vitamin K supplementation and there are further trials in progress. Patients on warfarin are particularly prone to CV calcification but there has been concern that supplementation would either counter warfarin treatment or destabilise INR. In fact, studies suggest that low dose phylloquinone did not increase coagulation and may improve the stability of anticoagulant therapy. Furthermore, use of oral anticoagulants which do not affect vitamin K metabolism, such as ximelagatran, could be used when there is a need for vitamin K supplementation for artery or bone health.

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Inactive Matrix Gla Protein Is Causally Related to Adverse Health Outcomes

Cited by 83 publications

References 46 publications

Inactive Matrix Gla-Protein Is Associated With Arterial Stiffness in an Adult Population–Based Study

Inactive Matrix Gla-Protein Is Associated With Arterial Stiffness in an Adult Population–Based Study

Vitamin-K-Dependent Protection of the Renal Microvasculature: Histopathological Studies in Normal and Diseased Kidneys

Cardiovascular Calcification and Bone: A Comparison of the Effects of Dietary and Serum Vitamin K and its Dependent Proteins

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