Role of Vitamin K2 in managing vascular calcification: Review

Calcification is common in the elderly population, and patients suffering from diseases such as chronic kidney disease, diabetes, aortic stenosis, and atherosclerosis (2). The presence of calcium depositions in the wall of an artery of the human body contributes to nearly 4-fold risk for Cardiovascular (CV) mortality and a 3.4-fold risk for any CV event. (3)

Despite being seen as a passive process for a long time, in recent years it has become clear that Vascular Calcification is an active, ongoing process involving regulatory proteins and molecules that either promote or inhibit the deposition and accumulation of calcium and hydroxyapatite within the vessel wall. (4)

Vitamin K–dependent proteins are integral to the regulation of arterial stiffness. Matrix Gla protein (MGP) and Gla-rich protein, two important proteins that regulate and prevent vascular calcification, require vitamin K as a cofactor for gamma-carboxylation—an essential step in their activation. (5,6) Other proteins requiring vitamin K for activation, such as osteocalcin and Gas6, (7) are also involved in bone and mineral metabolism. Studies have repeatedly supported the fact that both cardiovascular calcification and MGP activity are directly correlated with vitamin K2 intake (8, 9).

Previous studies have focused exclusively on the fact that vitamin K1 (phylloquinone) is essential for coagulation factor synthesis, thus making the present recommended dietary allowances based on it. On the contrary, despite a growing body of data (10) suggesting that extra-hepatic tissues such as bone and vessel wall require higher dietary intakes and have a preference specifically for menaquinone (Vitamin K2), this aspect has not been evaluated thoroughly.

Though some mammalian tissues (notably testis, pancreas, and arterial vessel wall) possess the remarkable ability to convert phylloquinone into menaquinone, the maximum requirement of Vitamin K2 is met through diet.

Addressing the question of whether experimental animals (rats) exhibit a tissue-specific use of either phylloquinone or menaquinones, L. J. Schurgers et al (11), in 2001, undertook a study to rationalize a standardized intake of vitamin K2 that adequately suffice for the extrahepatic (notably vascular) tissue requirements.

In the experiments, Menaquinone 4 (MK-4), the predominant homolog of vitamin K2, has been used as a representative of the group of menaquinones.

Tissue-specific vitamin K consumption under controlled intake was determined in warfarin- treated rats using the vitamin K-quinone/epoxide ratio as a measure for vitamin K consumption.

The authors reported the production of a monoclonal antibody raised against a synthetic peptide homologous to the amino acid sequence 3 – 15 in human MGP, designated as mAb 3–15. Immunohistochemical analysis of human vascular material, both healthy and atherosclerotic coronary arteries, was performed using this monoclonal antibody against MGP. The same antibody was used for the quantification of MGP levels in serum.

1. Some extrahepatic tissues including the arterial vessel wall have a high preference for accumulating and using menaquinone rather than phylloquinone.

2. Both intima and media sclerosis is associated with high tissue concentrations of MGP, with the most prominent accumulation at the interface between vascular tissue and calcified material. This strong MGP expression suggests that the contact between tissue and calcium salt crystal is a common trigger in this process of sclerosis. When analyzing early phases of calcification in peripheral arteries of diabetics, it became apparent that the elastic lamellae were the first sites of calcium deposition.

3. Moreover, in these experiments, MGP expression seemed to be inversely correlated to calcification. This further supported the idea that tissue calcification is retarded by MGP.

4. This was consistent with increased concentrations of circulating MGP in subjects with atherosclerosis and diabetes mellitus.

 In a substantial part of the adult population, the arterial vitamin K supply is marginal so that at increased MGP synthesis (as a response to tissue calcification) the vitamin K status of the arterial vessel wall is inadequate to support full MGP carboxylation. This means that mainly undercarboxylated, non-functional MGP is produced which is incapable of retarding the calcification process.

 Vascular vitamin K-deficiency was noted in subjects with normal hemostasis implying the concept of tissue-defined vitamin K requirement. They pointed out that even when the hepatic vitamin K supply is sufficient to support full carboxylation of the blood coagulation factors, other tissues may produce Gla-proteins in an undercarboxylated form, indicating their specific need of vitamin K2. This further suggests a specific transport to and uptake of vitamin K2 by extra-hepatic tissues.

 The authors highlighted the fact that when data on menaquinone content of common foods were recently added to the Rotterdam Study (12) database, it showed strong and increasing protection against cardiovascular disease from the lowest to the highest quartile of menaquinone (and not phylloquinone) intake. Taken together these data strongly suggest that for the vessel wall menaquinones are more important.

 Since no RDA value for dietary menaquinone intake of VIT K2 had been defined previously, the researchers, based on their observations, recommended that menaquinone intake should be increased to 45 μg/day besides the standard RDA of vitamin K1.

"We recommend that menaquinone intake should be increased to 45 μg/day, which is comparable to the amount present in 60 g of cheese or curd cheese or 4 g of natto. If a similar definition would be applied for vitamin K1, the RDA value would increase from 60 to 375 μg/day, which is comparable to 100–200 g of green vegetables per day," the authors concluded

This was the very first study of its kind reporting a direct link between vascular calcification and MGP, while further pointing out the role of a standardized, adequate intake of vitamin K2 to prevent the disease progression.

1. Inhibitors of calcification in blood and urine.Schlieper G, Westenfeld R, Brandenburg V, Ketteler M Semin Dial. 2007 Mar-Apr; 20(2):113-21

2. Proudfoot D, Shanahan CM. Biology of calcification in vascular cells: intima versus media. Herz 2001; 26: 245–251.

3. Vascular calcifications as a marker of increased cardiovascular risk: a meta-analysis.Rennenberg RJ, Kessels AG, Schurgers LJ, van Engelshoven JM, de Leeuw PW, Kroon AA Vasc Health Risk Manag. 2009; 5(1):185-97.

4. Temmar M, Liabeuf S, Renard C, Czernichow S, Esper NE, Shahapuni I, et al: Pulse wave velocity and vascular calcification at different stages of chronic kidney disease. J Hypertens 28: 163–169, 2010.

5. Viegas CS, Rafael MS, Enriquez JL, Teixeira A, Vitorino R, Luís IM, et al: Gla-rich protein acts as a calcification inhibitor in the human cardiovascular system. Arterioscler Thromb Vasc Biol 35: 399–408, 2015

6. Furie B, Furie BC (1990) Molecular basis of vitamin K-dependent g-carboxylation. Blood 75: 1753–62

7. Kaesler N, Immendorf S, Ouyang C, Herfs M, Drummen N, Carmeliet P, et al: Gas6 protein: Its role in cardiovascular calcification. BMC Nephrol 17: 52, 2016

8. Geleijnse JM, et al. Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study. J Nutr 2004; 134,3100–3105.

9. Schurgers LJ, et al. Regression of warfarin-induced medial elastocalcinosis by high intake of vitaminK in rats. Blood 2007; 109: 2823–2831.

10. Reedstrom CK, Suttie JW (1995) Comparative distribution, metabolism, and utilization of phylloquinone and menaquinone-9 in the rat liver. Proc Soc Exptl Biol Med 209: 403- 9

11. Schurgers, LJ, Dissel, PE, Spronk, HM, Soute, BA, Dhore, CR, Cleutjens, JP & Vermmer, C (2001) Role of vitamin K and vitamin K-dependent proteins in vascular calcification. Z Kardiol 90, Suppl. 3, 57–63