ReviewPrevention of vasculopathy by vitamin K supplementation: Can we turn fiction into fact?
Introduction
Although vitamin K has originally emerged from a pure hemostasiological cofactor required to activate clotting factors, it is also a key factor in the regulation of bone and soft tissue calcification based on the anti-calcific property of vitamin K due to its ability to activate matrix-Gla protein (MGP). The unequivocal role of vitamin K is to function as cofactor in the post-translational gamma-glutamylcarboxylation of specific protein bound glutamate residues. Hence, these proteins are called vitamin K-dependent proteins (Gla-proteins). Data from epidemiological studies have pointed out to an important role of Vitamin K as a potentially protective factor for cardiovascular health [1], [2]. Replenishment of vitamin K via increased dietary intake or oral substitution is relatively easy and cost effective and thus it is intriguing to speculate about a favorable risk-benefit ratio. Vitamin K supplementation appears to be safe and the WHO has set no upper tolerance level for vitamin K intake [3]. Moreover, long-term high dosage therapy with vitamin K is not associated with increased thromboembolic events and no elevated event rate was recorded even with 45 mg vitamin K-2 (menatetrenone) daily for three years in 2185 postmenopausal osteoporotic women [4]. Prior to advise on recommendations for vitamin K supplementation, however, several gaps in evidence need to be acknowledged. Fig. 1 depicts a step-by-step approach of vitamin K replenishment from biological plausibility to large-scale evidence-providing, interventional, randomized-controlled trials (RCTs). We will guide the reader on this road and focus on ongoing clinical research in the vitamin K arena.
Section snippets
Vitamin K, MGP and vascular health
Research investigating the role of vitamin K in vascular biology started some 20 years ago. Luo and coworkers were the first to show that MGP deficiency in mice resulted in vascular calcification at the elastic lamellae of the aortic wall starting as early as two weeks after birth. MGP-deficient animals died prematurely due to rupture of the heavily calcified aorta [5]. Only one year later, Price and colleagues showed that the chemical inhibition of MGP function by the vitamin K-antagonist
In case vitamin K is good and K insufficiency is bad, is antagonizing K the ugly?
As described above, nutritional vitamin K status is linked to vascular health. Further demonstration of the importance of vitamin K for vasculature health comes from fundamental in vitro and in vivo work demonstrating that the use of vitamin K antagonists (VKA) for oral anticoagulation therapy (OAT) accelerates cardiovascular calcification [16], [17], [18], [19], [20]. In rats with warfarin-induced medial elastocalcinosis, high intake of vitamin K-1 and K-2 for 6 weeks reversed calcification,
Vitamin K substitution – basic considerations
Vitamin K, a fat soluble vitamin, exists in various forms, i.e. K-1 and K-2. Vitamin K-1 is found in green vegetables and typically supplied by vegetarian diet whereas vitamin K-2 is produced by bacteria (in the intestine and in fermented foods). Vitamin K is transported by lipids (triacylglycerol-rich lipoprotein) from the intestine to the liver then to the periphery via LDL cholesterol. The K-2 vitamins MK-4 and MK-7 are commonly used as supplements in both animal and human studies. Some data
Filling vitamin K storage pool by supplementation: biochemical effects
Regarding vitamin K research patients with end-stage renal disease are of particularly interest since vitamin K status is low and cardiovascular event rate extraordinarily high [35] in these patients. Two recent studies investigated effects of vitamin K replenishment in hemodialysis patients [36], [37]. Westenfeld et al. reported in a randomized trial effects of daily vitamin K-2 supplementation on vitamin K-dependent proteins in 53 hemodialysis patients [37]. Carboxylation status of MGP,
Vitamin K substitution in ongoing clinical trials investigating cardiovascular endpoints
As described above, preclinical and epidemiological data set the stage for a role of vitamin K in maintaining vascular health. This prompted researchers to investigate vitamin K supplementation in interventional trials looking at vascular function and calcification. The first published small interventional trial is published as abstract (Ilona Kurnatowska et al.; ERA-EDTA abstract 2013). In this study, 42 CKD patients stage 3–5 were randomized into two treatment arms: one group receiving 10 μg
Ongoing clinical trials investigating the distinct role of non-vitamin K-antagonist oral anticoagulants (NOACs) and vitamin K antagonist in the genesis of vascular disease
Thrombosis has been implicated in the development of cardiovascular disease [41]. Based on the abovementioned arguments that vitamin K exerts beneficial cardiovascular effects and that vitamin K deficiency causes vascular calcification, treatment of hypercoagulability without VKA might even benefit cardiovascular health. Advantage and superiority of NOAC treatment (i.e. apixaban, rivaroxaban, dabigatran, edoxaban) over VKA is a matter of ongoing debate. Multiple meta-analyses have been reported
Conflict of interest
None.
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2021, Biochemical Engineering JournalCirculating phylloquinone, inactive Matrix Gla protein and coronary heart disease risk: A two-sample Mendelian Randomization study
2020, Clinical NutritionCitation Excerpt :Matrix Gla protein (MGP) is a vitamin K dependent protein since it requires vitamin K for activation [5]. Inactive MGP, dephosphorylated uncarboxylated MGP (dp-ucMGP), serves as a circulating marker for vitamin K, where low dp-ucMGP levels represents long term high vitamin K intake [6]. Both phylloquinone and menaquinone supplementation substantially reduce dp-ucMGP levels [7].
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2019, Advances in Chronic Kidney DiseaseCitation Excerpt :Statins interact with vitamin K metabolism. Vitamin K supports the activity of an important anticalcification factor in the vascular wall: matrix-Gla protein (MGP).30 MGP requires vitamin K, especially vitamin K2, for post-translational gamma-carboxylation and full biological activity.30
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2019, Clinical Nutrition ESPENCitation Excerpt :For example, the disadvantage of using serum phylloquinone concentration in isolation to evaluate vitamin K status only represents the abundance of a single vitamer, rather than all K vitamins. The putative health roles of the vitamin K2 series, the prokaryotic origins and sources of which are distinct from that of the plant-synthesized phylloquinone, are beginning to be better understood [25]. Further, phylloquinone measurement alone as a biomarker also suffers from its association with serum lipids and does not reflect the metabolic conversion of phylloquinone to menaquinone-4 in humans [26].
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