Vitamin K: Double Bonds beyond Coagulation Insights into Differences between Vitamin K1 and K2 in Health and Disease

Halder, Maurice; Petsophonsakul, Ploingarm; Akbulut, Asim Cengiz; Pavlic, Angelina; Bohan, Frode; Anderson, Eric; Maresz, Katarzyna; Kramann, Rafael; Schurgers, Leon J.

doi:10.3390/ijms20040896

Cited by 174 publications

(172 citation statements)

References 111 publications

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Section: Introductionmentioning

confidence: 99%

“…In addition to activating various VKDPs, vitamin K acts as an antioxidant [13] and vitamin K2 or menaquinone-4 (MK-4) acts as a ligand of the steroid and xenobiotic receptor/pregnenolone X receptor (SXR/PXR) [14,15]. Thus, vitamin K is expected to have various health benefits [13], preventing or alleviating cardiovascular disease, bone fracture, diabetes mellitus, cancer, liver disease, chronic kidney disease, immune disorder, neurological disease, and obesity. γ-carboxyglutamic acid-rich protein Inhibition of ectopic calcification, anti-inflammatory [5] Periostin Inhibition of ectopic calcification, tissue regeneration [6] Growth arrest-specific protein 6 Cell proliferation [7,8] Proline-rich γ-carboxy glutamyl proteins 1 and 2 Not well-known [9,10] γ-glutamyl carboxylase γ-glutamyl carboxylation of vitamin K-dependent proteins [11] Recently, vitamin K2 (MK-7) has been found to be highly effective in activating extrahepatic VKDPs at nutritional doses.…”

Section: Introductionmentioning

confidence: 99%

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MK-7 and Its Effects on Bone Quality and Strength

Sato¹,

Inaba²,

Yamashita³

2020

Nutrients

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Vitamin K acts as a cofactor and is required for post-translational γ-carboxylation of vitamin K-dependent proteins (VKDP). The current recommended daily intake (RDI) of vitamin K in most countries has been established based on normal coagulation requirements. Vitamin K1 and menaquinone (MK)-4 has been shown to decrease osteocalcin (OC) γ-carboxylation at RDI levels. Among the several vitamin K homologs, only MK-7 (vitamin K2) can promote γ-carboxylation of extrahepatic VKDPs, OC, and the matrix Gla protein at a nutritional dose around RDI. MK-7 has higher efficacy due to its higher bioavailability and longer half-life than other vitamin K homologs. As vitamin K1, MK-4, and MK-7 have distinct bioactivities, their RDIs should be established based on their relative activities. MK-7 increases bone mineral density and promotes bone quality and strength. Collagen production, and thus, bone quality may be affected by MK-7 or MK-4 converted from MK-7. In this review, we comprehensively discuss the various properties of MK-7.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MK-7 and Its Effects on Bone Quality and Strength

Sato¹,

Inaba²,

Yamashita³

2020

Nutrients

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“…There are two naturally occurring vitamers of vitamin K, that differ in bioavailability and distribution in the human body: vitamin K1 (phylloquinone) and vitamin K2 (menaquinone, MK). While the former is mainly retained in the liver to serve as a cofactor for the carboxylation of clotting factors, circulating vitamin K2 is available for the extrahepatic tissue and the vascular system [72] and thereby is more capable of acting in the vascular calcification process [70]. Due to its bioavailability, the vitamer MK-7 is mainly used in clinical trials [72].…”

Section: Vitamin Kmentioning

confidence: 99%

“…While the former is mainly retained in the liver to serve as a cofactor for the carboxylation of clotting factors, circulating vitamin K2 is available for the extrahepatic tissue and the vascular system [72] and thereby is more capable of acting in the vascular calcification process [70]. Due to its bioavailability, the vitamer MK-7 is mainly used in clinical trials [72]. A single-MK-7 treatment, as well as the combination of MK-7 and eicosapentaenoic, reduced the development of vascular calcification in an experimental model of adenine-induced CKD rats ( Table 2) [66].…”

Section: Vitamin Kmentioning

confidence: 99%

Cardiovascular Calcification in Chronic Kidney Disease—Therapeutic Opportunities

Himmelsbach

Ciliox

Goettsch

2020

Toxins

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Patients with chronic kidney disease (CKD) are highly susceptible to cardiovascular (CV) complications, thus suffering from clinical manifestations such as heart failure and stroke. CV calcification greatly contributes to the increased CV risk in CKD patients. However, no clinically viable therapies towards treatment and prevention of CV calcification or early biomarkers have been approved to date, which is largely attributed to the asymptomatic progression of calcification and the dearth of high-resolution imaging techniques to detect early calcification prior to the ‘point of no return’. Clearly, new intervention and management strategies are essential to reduce CV risk factors in CKD patients. In experimental rodent models, novel promising therapeutic interventions demonstrate decreased CKD-induced calcification and prevent CV complications. Potential diagnostic markers such as the serum T50 assay, which demonstrates an association of serum calcification propensity with all-cause mortality and CV death in CKD patients, have been developed. This review provides an overview of the latest observations and evaluates the potential of these new interventions in relation to CV calcification in CKD patients. To this end, potential therapeutics have been analyzed, and their properties compared via experimental rodent models, human clinical trials, and meta-analyses.

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“…The most important function of vitamin K is to serve as a cofactor in the synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X in the liver [4,5]. Activation of vitamin K-dependent proteins (VKDPs) is mediated through the conversion of glutamic acid (Glu) residue of their molecules to γ-carboxyglutamic acid (Gla) by the action of γ-glutamyl carboxylase (GGCX).…”

Section: Introductionmentioning

confidence: 99%

The Inhibitory Roles of Vitamin K in Progression of Vascular Calcification

et al. 2020

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Vitamin K is a fat-soluble vitamin that is indispensable for the activation of vitamin K-dependent proteins (VKDPs) and may be implicated in cardiovascular disease (CVD). Vascular calcification is intimately associated with CV events and mortality and is a chronic inflammatory process in which activated macrophages promote osteoblastic differentiation of vascular smooth muscle cells (VSMCs) through the production of proinflammatory cytokines such as IL-1β, IL-6, TNF-α, and oncostatin M (OSM) in both intimal and medial layers of arterial walls. This process may be mainly mediated through NF-κB signaling pathway. Vitamin K has been demonstrated to exert anti-inflammatory effects through antagonizing NF-κB signaling in both in vitro and in vivo studies, suggesting that vitamin K may prevent vascular calcification via anti-inflammatory mechanisms. Matrix Gla protein (MGP) is a major inhibitor of soft tissue calcification and contributes to preventing both intimal and medial vascular calcification. Vitamin K may also inhibit progression of vascular calcification by enhancing the activity of MGP through facilitating its γ-carboxylation. In support of this hypothesis, the procalcific effects of warfarin, an antagonist of vitamin K, on arterial calcification have been demonstrated in several clinical studies. Among the inactive MGP forms, dephospho-uncarboxylated MGP (dp-ucMGP) may be regarded as the most useful biomarker of not only vitamin K deficiency, but also vascular calcification and CVD. There have been several studies showing the association of circulating levels of dp-ucMGP with vitamin K intake, vascular calcification, mortality, and CVD. However, additional larger prospective studies including randomized controlled trials are necessary to confirm the beneficial effects of vitamin K supplementation on CV health.

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Vitamin K: Double Bonds beyond Coagulation Insights into Differences between Vitamin K1 and K2 in Health and Disease

Cited by 174 publications

References 111 publications

MK-7 and Its Effects on Bone Quality and Strength

MK-7 and Its Effects on Bone Quality and Strength

Cardiovascular Calcification in Chronic Kidney Disease—Therapeutic Opportunities

The Inhibitory Roles of Vitamin K in Progression of Vascular Calcification

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