Vascular calcification is characterized by mineral depositions on the walls in the vascular system; the depositions present are of calcium phosphate complexes in the form of hydroxyapatite ( El Asmar et al., 2014). Based on recent clinical and pre-clinical studies, Abdullah et al. highlighted the potential cellular and physiological roles of vitamin K in cardiovascular diseases (CVD), and highlighted the association between CVD prevention and vitamin K supplementation ( Al-Suhaimi and Al-Jafary, 2020). Matrix Gla protein (MGP) plays a key role in inhibition of vascular calcification; it has the potential to inhibit as well as to reverse the process of calcification. MGP undergoes post-translational modifications like phosphorylation and carboxylation which result in the activation of MGP from its inactive state. Serine residues present on MGP are phosphorylated by casein kinase, this results in secretion of MGP in the extracellular matrix ( Roumeliotis et al., 2019). In addition, activation of MGP takes place when glutamate residues present on MGP undergo carboxylation by γ-carboxylase. Vitamin K2-7 is the cofactor of γ-carboxylase, hence, plays an important role in activation of MGP. Negatively charged MGP has high affinity towards free calcium present in the blood vessels. It binds directly to the circulating calcium and hydroxyapatite crystals that are accumulated in the walls of the vessels forming inactive complexes ( Roumeliotis et al., 2020). Negatively charged MGP has high affinity towards free calcium present in the blood vessels. It binds directly to the circulating calcium and hydroxyapatite crystals that are accumulated in the walls of the vessels forming inactive complexes ( Roumeliotis et al., 2020). MGP initiates autophagic clearance by attracting macrophages and phagocytes ( Shanahan, 2005). In addition, MGP removes free circulating calcium and leads it to the bone. Furthermore, MGP inhibits vascular calcification through downregulation of bone morphogenetic protein-2 (BMP-2) which promotes vascular calcification. Transformation of VSMCs to an osteoblastic phenotype is triggered by BMP-2 and is found within the walls of calcified arteries ( Boström et al., 1993). MGP is in inactive state and requires vitamin K2-7 for γ-carboxylation of its glutamic acid (Glu) into γ-carboxyglutamate (Gla). When Glu is transformed into Gla, molecular changes occur in the structure of MGP which in turn activates it. Further, to become biologically active, MGP undergoes phosphorylation of serine residues. Phosphorylation is dependent on vitamin K and is considered as the most critical step in activation of MGP. Therefore, to gain the ability to bind to hydroxyapatite, calcium and BMP-2 MGP is required to be carboxylated as well as phosphorylated ( Figure 4) ( Wallin et al., 2000). Furthermore, vascular calcification is also associated with activation of growth arrest-specific gene 6 (Gas6) activated by vitamin K2. Gas6 undergoes γ-carboxylation by vitamin K2 to trigger anti-apoptotic activity of Bcl-2. Gas6 also inhibits caspase 3, a pro-apoptotic protein, thus preventing the apoptosis induced by calcification and starvation of fibroblasts ( Villa et al., 2017). Gas6 and other growth factors act as growth promoters in VMSCs. Furthermore, OAC is often linked to undesired soft-tissue calcification in both children and adults. [27] [28] This process has been shown to be dependent upon the action of K vitamins. Vitamin K deficiency results in undercarboxylation of MGP. Also in humans on OAC treatment, two-fold more arterial calcification was found as compared to patients not receiving vitamin K antagonists. [29] [30] Among consequences of anticoagulant treatment: increased aortic wall stiffness, coronary insufficiency, ischemia, and even heart failure. Arterial calcification might also contribute to systolic hypertension and ventricular hypertrophy. [31] [32] Anticoagulant therapy is usually instituted to avoid life-threatening diseases, and high vitamin K intake interferes with anticoagulant effects. [ citation needed] Patients on warfarin (Coumadin) or being treated with other vitamin K antagonists are therefore advised not to consume diets rich in K vitamins. [ citation needed] In other organisms [ edit ] But if you’re looking to add more vitamin K2 to your diet, know that some of the top sources of vitamin K-rich foods aren’t ones we typically see as part of a healthy diet. Whereas vitamin K1 is abundant in leafy greens and other “health food s , “ vitamin K2 is found in a lot of foods that aren’t typically recommended as part of a heart-healthy diet. Pucaj K, Rasmussen H, Møller M, Preston T (September 2011). "Safety and toxicological evaluation of a synthetic vitamin K2, menaquinone-7". Toxicology Mechanisms and Methods. 21 (7): 520–32. doi: 10.3109/15376516.2011.568983. PMC 3172146. PMID 21781006.

Mahdinia et al. studied the key growth factors required for improving the production of vitamin K2-7 in biofilm reactors using B. subtilis natto. The growth factors included optimum pH, temperature and agitation. The medium used for the production was glycerol-based as it is relatively cheaper compared to other carbon sources like sucrose, glucose and mannose and can also improve the production of vitamin K2-7. The optimum growth parameters reported were pH: 6.58, temperature: 35°C and agitation: 200 rotations per minute (rpm). An increase of 58% in the concentration of vitamin K2-7 was observed when growth parameters were optimized ( Mahdinia et al., 2018). All K vitamins are similar in structure: they share a " quinone" ring, but differ in the length and degree of saturation of the carbon tail and the number of repeating isoprene units in the "side chain". [8] [ full citation needed] The number of repeating units is indicated in the name of the particular menaquinone (e.g., MK-4 means that four isoprene units are repeated in the carbon tail). The chain length influences lipid solubility and thus transport to different target tissues. Based on animal studies and the role vitamin K2 plays in bone metabolism, it’s reasonable to assume that this nutrient affects dental health as well. While much is still to be learned about vitamin K2, the signs so far point to an underutilized and underappreciated powerhouse for our bodies. Carboxylation of these vitamin K-dependent Gla-proteins, besides being essential for the function of the protein, is also an important vitamin recovery mechanism since it serves as a recycling pathway to recover vitamin K from its epoxide metabolite (KO) for reuse in carboxylation.

Conflict of Interest

Vitamin K has been shown to help activate a protein that helps prevent calcium from depositing in your arteries,” Zumpano explains. “Calcium deposits contribute to the development of plaque, so vitamin K does a lot of good for your heart health.” Ranmadugala et al. studied the Bacillus subtilis fermentation for high production of K2-7 using biocompatible organic solvents, n-hexane and n-butanol mixture. A ∼1.7-fold increase of total K2-7 was observed when compared to the control. Further, effect of 3-aminopropyltriethoxysilane-coated ferric oxide nanoparticles was studied on K2-7 production using Bacillus subtilis (ATCC 6633). The production as well as yield of K2-7 showed a significant increase when the strain was treated with 3-aminopropyltriethoxysilane-coated ferric oxide nanoparticles. An increase in yield by 2-fold was obtained compared to the fermentation medium containing untreated bacterial strain ( Ranmadugala et al., 2018). Degree of saturation and number of isoprene units vary with the organism that synthesizes the compound ( Beulens et al., 2013).

Vitamin K1 comes from plant sources, like leafy greens and blueberries. While vitamin K2 is more common in animal products, fermented foods and some kinds of cheese. It stays in your body longer than vitamin K1 and holds the potential for some serious health benefits that are just now starting to come to light. I think we’ve always known that there’s a vitamin K2, I just don’t think we’ve really ever given it enough credit for how much work it does in the body,” says registered dietitian Julia Zumpano, RD, LD. A study was carried out by Aoun et al. to determine the level of dp-ucMGP, after treatment using MK-7 in haemodialysis patients. It is known that dp-ucMGP increases in vitamin K-deficient patients which can be associated with vascular calcification. Hence, 50 haemodialysis patients from Eastern Mediterranean cohort were administered 360µg of MK-7 for 4weeks. The results indicated 86% decrease of dp-ucMGP after 4weeks of treatment; however, further studies are required to assess the change of vascular calcification after longer duration of treatment ( Aoun et al., 2017). Also, a randomized dose-finding study was performed in 200 chronic hemodialysis patients. Patients were administered MK-7 with either 360, 720 or 1080µg thrice weekly for 8weeks. It was observed that decrease in dp-ucMGP was 17, 33 and 46% respectively indicating a dose dependent response by MK-7 supplementation. Few side-effects that were reported were mild and independent of the dose ( Caluwe et al., 2014). Likewise, a randomized trial was carried out in 53 hemodialysis patients in which 45, 135 or 360µg of MK-7 was administered daily for 6weeks and compared with 50 healthy patients (control group). After 6weeks of treatment, the plasma levels of the hemodialysis patients were assessed which indicated the level of dp-ucMGP and ucOC was 4.5- and 8.4-fold respectively higher than the control group. Forty-nine patients showed elevation in the protein induced by vitamin K absence II (PIVKA-II). It was also observed that MK-7 supplementation showed a dose- and time-dependent response in dp-ucMGP and ucOC and PIVKA-II levels ( Westenfeld et al., 2012). Supplement companies sell nattō extract reportedly standardized with regards to K 2 content, in capsule form. [ citation needed] Analysis of foods [ edit ] Food MK-4 or MK-7 has a protective effect on bone mineral density and reduced risk of hip, vertebral and non-vertebral fractures. [10] These effects appear to be accentuated when combined with vitamin D and in the setting of osteoporosis. [1] Utilisation [ edit ]Plantalech L, Guillaumont M, Vergnaud P, Leclercq M, Delmas PD (November 1991). "Impairment of gamma carboxylation of circulating osteocalcin (bone gla protein) in elderly women". Journal of Bone and Mineral Research. 6 (11): 1211–6. doi: 10.1002/jbmr.5650061111. PMID 1666807. S2CID 21412585. A 2020 review about the association between dietary vitamin K and risks of coronary heart disease in adults found a lower risk of coronary heart disease with vitamin K supplementation. Rich animal sources include high fat dairy products from grass-fed cows and egg yolks, as well as liver and other organ meats ( 23).

Caraballo PJ, Gabriel SE, Castro MR, Atkinson EJ, Melton LJ (1999). "Changes in bone density after exposure to oral anticoagulants: a meta-analysis". Osteoporosis International. 9 (5): 441–8. doi: 10.1007/s001980050169. PMID 10550464. S2CID 12494428.Zumpano helps us understand the health benefits of vitamin K2 and how to get more of it in your diet. What is vitamin K2? The benefits of supplementing with K2 may be enhanced even further when combined with a vitamin D supplement. These two vitamins have synergistic effects, which means they may work together ( 25). The effect of MK-7 supplementation on the activity of vitamin K-dependent procoagulant factors was investigated by Ren et al. ( Ren et al., 2021). Forty healthy volunteers were administered 90µg of menaquinone-7 for 30days; and prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), blood coagulation factors II, VII, IX and X activities and protein induced by vitamin K absence or antagonist-II (PIVKA-II) were measured in blood samples. The results indicated that supplementation of MK-7 at the recommended dose does not affect the vitamin K dependent coagulation factors ( Ren et al., 2021). In a clinical study, Zhelyazkova-Savova et al. ( Zhelyazkova-Savova et al., 2021) examined the effects of statin drug on vitamin K2 status and VKDPs. It was observed that the levels of uncarboxylated osteocalcin (ucOC) and ucOC:cOC ratio increased in patients that were administered with statin. In addition, statin inhibited activity of VKDPs and calcium accumulation was increased in arterial walls. A study conducted by Zhang et al., 2012. determined the synergistic effect of sorafenib and vitamin K2 on human hepatocellular carcinoma (HepG2) cells. In vitro, co-administration of 2.5µM sorafenib with 1µM vitamin K2 synergistically inhibited the HepG2 cell proliferation. In vivo study was carried out in nude mice by inoculation of EGFP-expressing HepG2 cells. Sorafenib (1.25mg/kg body weight) and vitamin K2 (2mg/kg body weight) were injected daily for 18days. It was observed that sorafenib and vitamin K2 inhibited the tumor growth synergistically in combination therapy. In a study conducted by Hara et al. in rat aorta loop model, it was observed that when vitamin K2 (1.5, 14 and 145mg/kg) and warfarin (0.80mg/L) were administered simultaneously, the high dose of K2 (145mg/kg) reduced the effect of warfarin on thrombosis suggesting on interaction between K2 and warfarin ( Hara et al., 1999). A study was carried out by Theuwissen et al. to determine the effect of MK-7 supplementation on vitamin K antagonist therapy (VKA). Eighteen healthy volunteers were administered with increasing doses (10–20–45µg) of MK-7 for 6weeks after previous treatment with acenocoumarol for 4weeks. The study reported that MK-7 supplementation as low as 10µg should be avoided during VKA as it can significantly affect the anticoagulation sensitivity in few individuals ( Theuwissen et al., 2013). Further, a study was designed to determine the effective role of MK-7 in the therapeutic management of rheumatoid arthritis (RA). Eighty-four patients undergoing RA treatment were either administered 100µg dose of MK-7 capsules or kept naïve without changing any other medication for 3months. The clinical and biochemical markers like ucOC, erythrocyte sedimentation rate (ESR), disease activity score assessing 28 joints with ESR (DAS28-ESR), C-reactive protein and matrix metalloproteinase (MMP-3) were assessed using patients’ serum. There was a significant decrease in clinical and biochemical markers such as ucOC, ESR and DAS28-ESR for moderate and good responders compared to non-responders. The results indicated that there was improvement in disease activity score of RA by changing the bone mineral metabolism when treated with MK-7 ( Abdel-Rahman et al., 2015). Ozdemir et al. conducted a pilot study to investigate the therapeutic effect of dietary supplement of vitamin D (5µg calcitriol) and vitamin K2 (50µg MK-7) in 20 children on thalassemic osteopathy (TOSP). The serum samples collected after 6 and 12months showed decrease in the ratio of ucOC to cOC; however, it was not significant ( Ozdemir et al., 2013). Summeren et al. conducted a double blind randomized placebo-controlled trial to determine the effect of MK-7 supplementation on 55 pre-pubertal children aged between 6 and 10years from Netherlands. 45µg of MK-7 was administered daily for 8weeks and compared with placebo group. The serum samples showed increase in MK-7 and decrease in circulating ucOC concentration ( van Summeren et al., 2009). Clinical Trials on K2-7 The reported amounts in comparable milk from the USA and the Netherlands differ by more than 40 times, so these numbers should be considered suspect. Shearer, Martin J.; Newman, Paul (March 2014). "Recent trends in the metabolism and cell biology of vitamin K with special reference to vitamin K cycling and MK-4 biosynthesis". Journal of Lipid Research. 55 (3): 345–362. doi: 10.1194/jlr.R045559. ISSN 0022-2275. PMC 3934721. PMID 24489112.