Vitamin K as a Powerful Micronutrient in Aging and Age-Related Diseases: Pros and Cons from Clinical Studies

Dina C Simes, Carla S B Viegas, Nuna Araújo, Catarina Marreiros, Dina C Simes, Carla S B Viegas, Nuna Araújo, Catarina Marreiros

Abstract

Vitamin K is a multifunctional micronutrient implicated in age-related diseases such as cardiovascular diseases, osteoarthritis and osteoporosis. Although vitamin K-dependent proteins (VKDPs) are described to have a crucial role in the pathogenesis of these diseases, novel roles have emerged for vitamin K, independently of its role in VKDPs carboxylation. Vitamin K has been shown to act as an anti-inflammatory by suppressing nuclear factor κB (NF-κB) signal transduction and to exert a protective effect against oxidative stress by blocking the generation of reactive oxygen species. Available clinical evidences indicate that a high vitamin K status can exert a protective role in the inflammatory and mineralization processes associated with the onset and progression of age-related diseases. Also, vitamin K involvement as a protective super-micronutrient in aging and 'inflammaging' is arising, highlighting its future use in clinical practice. In this review we summarize current knowledge regarding clinical data on vitamin K in skeletal and cardiovascular health, and discuss the potential of vitamin K supplementation as a health benefit. We describe the clinical evidence and explore molecular aspects of vitamin K protective role in aging and age-related diseases, and its involvement as a modulator in the interplay between pathological calcification and inflammation processes.

Keywords: cardiovascular diseases; inflammaging; inflammation; pathological calcification; skeletal health; vitamin K; vitamin K-dependent proteins.

Conflict of interest statement

Dina C. Simes and Carla Viegas are cofounders of GenoGla Diagnostics. A PCT patent application PCT/PT2009000046, is owned by University of Algarve and the Centre of Marine Sciences (CCMAR) and the exclusive rights are licensed to GenoGla Diagnostics. The authors declare that there is no conflict of interests regarding the publication of this paper.

Figures

Figure 1
Figure 1
Vitamin K roles in health and disease. Vitamin K function as a co-factor for γ-glutamyl carboxylase enzyme (GGCX) essential for the γ-carboxylation of target vitamin K-dependent proteins (VKDPs), but also independent of GGCX as an anti-inflammatory and antioxidant agent. Uncarboxylated (uc) protein forms of VKDPs, such as GRP, MGP, OC and Gas6, have been implicated in several pathological processes occurring in multiple age-related diseases, while the γ-carboxylated form of these proteins (c) are known to have a health protective role. Glu, glutamic acid; Gla, γ-carboxyglutamic acid; IKK, nuclear factor κB kinase; NF-κB, nuclear factor κB.
Figure 2
Figure 2
Schematic representation of vitamin K involvement in ’inflammaging’ and age-related diseases. ’Inflammaging’ and its associated senescence-associated secretory phenotype (SASP) can be triggered by stress conditions such as reactive oxygen species (ROS), DNA damage and telomerase loss, resulting in increased oxidative stress, mitochondrial dysfunction, cell senescence and apoptosis. All these processes contribute to an increased low-grade inflammatory status at tissue and systemic levels. Decreased vitamin K levels have been associated to increased aging processes and age-related disorders, by interfering with the γ-carboxylation of VKDPs such as Gas6 and GRP involved in apoptosis and pathological calcification, and by modulating inflammation, oxidative stress and mitochondrial dysfunction independently of its activity as co-factor for γ-glutamyl carboxylase (GGCX). Abs, apoptotic bodies; OA, osteoarthritis; CVD, cardiovascular diseases.

References

    1. Nowicka B., Kruk J. Occurrence, biosynthesis and function of isoprenoid quinones. BBA Bioenerg. 2010;1797:1587–1605. doi: 10.1016/j.bbabio.2010.06.007.
    1. Nakagawa K., Hirota Y., Sawada N., Yuge N., Watanabe M., Uchino Y., Okuda N., Shimomura Y., Suhara Y., Okano T. Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme. Nature. 2010;468:117–121. doi: 10.1038/nature09464.
    1. Xv F., Chen J., Duan L., Li S. Research progress on the anticancer effects of vitamin K2. Oncol. Lett. 2018;15:8926–8934. doi: 10.3892/ol.2018.8502.
    1. Harshman S.G., Shea M.K. The role of vitamin k in chronic aging diseases: Inflammation, cardiovascular disease, and osteoarthritis. Curr. Nutr. Rep. 2016;5:90–98. doi: 10.1007/s13668-016-0162-x.
    1. Shea M.K., Booth S.L., Massaro J.M., Jacques P.F., D’Agostino R.B., Ordovas J.M., O’Donnell C.J., Kathiresan S., Vasan R.S., Benjamin E.J., et al. Vitamin K and vitamin D status: Associations with inflammatory markers in the Framingham Offspring Study. Am. J. Epidemiol. 2008;167:313–320. doi: 10.1093/aje/kwm306.
    1. Fujii S., Shimizu A., Takeda N., Oguchi K., Katsurai T., Shirakawa H., Komai M., Kagechika H. Systematic synthesis and anti-inflammatory activity of ω-carboxylated menaquinone derivatives--Investigations on identified and putative vitamin K₂ metabolites. Bioorg. Med. Chem. 2015;23:2344–2352. doi: 10.1016/j.bmc.2015.03.070.
    1. Ohsaki Y., Shirakawa H., Miura A., Giriwono P.E., Sato S., Ohashi A., Iribe M., Goto T., Komai M. Vitamin K suppresses the lipopolysaccharide-induced expression of inflammatory cytokines in cultured macrophage-like cells via the inhibition of the activation of nuclear factor κB through the repression of IKKα/β phosphorylation. J. Nutr. Biochem. 2010;21:1120–1126. doi: 10.1016/j.jnutbio.2009.09.011.
    1. Li J., Wang H., Rosenberg P.A. Vitamin K prevents oxidative cell death by inhibiting activation of 12-lipoxygenase in developing oligodendrocytes. J. Neurosci. Res. 2009;87:1997–2005. doi: 10.1002/jnr.22029.
    1. Cranenburg E.C., Schurgers L.J., Uiterwijk H.H., Beulens J.W., Dalmeijer G.W., Westerhuis R., Magdeleyns E.J., Herfs M., Vermeer C., Laverman G.D. Vitamin K intake and status are low in hemodialysis patients. Kidney Int. 2012;82:605–610. doi: 10.1038/ki.2012.191.
    1. Misra D., Booth S.L., Tolstykh I., Felson D.T., Nevitt M.C., Lewis C.E., Torner J., Neogi T. Vitamin K deficiency is associated with incident knee osteoarthritis. Am. J. Med. 2013;126:243–248. doi: 10.1016/j.amjmed.2012.10.011.
    1. Shea M.K., Kritchevsky S.B., Hsu F.C., Nevitt M., Booth S.L., Kwoh C.K., McAlindon T.E., Vermeer C., Drummen N., Harris T.B., et al. The association between vitamin K status and knee osteoarthritis features in older adults: The health, aging and body composition study. Osteoarthr. Cartil. 2015;23:370–378. doi: 10.1016/j.joca.2014.12.008.
    1. Shea M.K., Booth S.L., Weiner D.E., Brinkley T.E., Kanaya A.M., Murphy R.A., Simonsick E.M., Wassel C.L., Vermeer C., Kritchevsky S.B. Circulating vitamin K is inversely associated with incident cardiovascular disease risk among those treated for hypertension in the Health, Aging, and Body Composition Study (Health ABC) J. Nutr. 2017;147:888–895. doi: 10.3945/jn.117.249375.
    1. Zhang S., Guo L., Bu C. Vitamin K status and cardiovascular events or mortality: A meta-analysis. Eur. J. Prev. Cardiol. 2018;26:549–553. doi: 10.1177/2047487318808066.
    1. Hawker G.A., Croxford R., Bierman A.S., Harvey P.J., Ravi B., Stanaitis I., Lipscombe L.L. All-cause mortality and serious cardiovascular events in people with hip and knee osteoarthritis: A population based cohort study. PLoS ONE. 2014;9:e91286. doi: 10.1371/journal.pone.0091286.
    1. Nuesch E., Dieppe P., Reichenbach S., Williams S., Iff S., Jüni P. All cause and disease specific mortality in patients with knee or hip osteoarthritis: Population based cohort study. BMJ. 2011;342:d1165. doi: 10.1136/bmj.d1165.
    1. Marles R.J., Roe A.L., Oketch-Rabah H.A. US Pharmacopeial Convention safety evaluation of menaquinone-7, a form of vitamin K. Nutr. Rev. 2017;75:553–578. doi: 10.1093/nutrit/nux022.
    1. Card D.J., Gorska R., Cutler J., Harrington D.J. Vitamin K metabolism: Current knowledge and future research. Mol. Nutr. Food Res. 2014;58:1590–1600. doi: 10.1002/mnfr.201300683.
    1. Fusaro M., Gallieni M., Rizzo M.A., Stucchi A., Delanaye P., Cavalier E., Moysés R.M.A., Jorgetti V., Iervasi G., Giannini S., et al. Vitamin K plasma levels determination in human health. Clin. Chem. Lab. Med. 2017;55:789–799. doi: 10.1515/cclm-2016-0783.
    1. Shea M.K., Booth S.L. Concepts and controversies in evaluating vitamin K status in population-based studies. Nutrients. 2016;8:8. doi: 10.3390/nu8010008.
    1. Schurgers L.J., Vermeer C. Differential lipoprotein transport pathways of K-vitamins in healthy subjects. Biochim. Biophys. Acta. 2002;1570:27–32. doi: 10.1016/S0304-4165(02)00147-2.
    1. Braam L.A., Dissel P., Gijsbers B.L., Spronk H.M., Hamulyak K., Soute B.A., Debie W., Vermeer C. Assay for human matrix gla protein in serum: Potential applications in the cardiovascular field. Arterioscler. Thromb. Vasc. Biol. 2000;20:1257–1261. doi: 10.1161/01.ATV.20.5.1257.
    1. Schurgers L.J., Cranenburg E.C., Vermeer C. Matrix Gla-protein: The calcification inhibitor in need of vitamin K. Thromb. Haemost. 2008;100:593–603. doi: 10.1160/TH08-02-0087.
    1. Cranenburg E.C., Koos R., Schurgers L.J., Magdeleyns E.J., Schoonbrood T.H., Landewe R.B., Brandenburg V.M., Bekers O., Vermeer C. Characterisation and potential diagnostic value of circulating matrix Gla protein (MGP) species. Thromb. Haemost. 2010;104:811–822. doi: 10.1160/TH09-11-0786.
    1. Caluwé R., Vandecasteele S., Van Vlem B., Vermeer C., De Vriese A.S. Vitamin K2 supplementation in haemodialysis patients: A randomized dose-finding study. Nephrol. Dial. Transplant. 2014;29:1385–1390. doi: 10.1093/ndt/gft464.
    1. Boxma P.Y., van den Berg E., Geleijnse J.M., Laverman G.D., Schurgers L.J., Vermeer C., Kema I.P., Muskiet F.A., Navis G., Bakker S.J., et al. Vitamin k intake and plasma desphospho-uncarboxylated matrix Gla-protein levels in kidney transplant recipients. PLoS ONE. 2012;7:e4799. doi: 10.1371/journal.pone.0047991.
    1. Westenfeld R., Krueger T., Schlieper G., Cranenburg E.C., Magdeleyns E.J., Heidenreich S., Holzmann S., Vermeer C., Jahnen-Dechent W., Ketteler M., et al. Effect of vitamin K2 supplementation on functional vitamin K deficiency in hemodialysis patients: A randomized trial. Am. J. Kidney Dis. 2012;59:186–195. doi: 10.1053/j.ajkd.2011.10.041.
    1. Dalmeijer G.W., van der Schouw Y.T., Magdeleyns E., Ahmed N., Vermeer C., Beulens J.W. The effect of menaquinone-7 supplementation on circulating species of matrix Gla protein. Atherosclerosis. 2012;225:397–402. doi: 10.1016/j.atherosclerosis.2012.09.019.
    1. Delanaye P., Krzesinski J.M., Warling X., Moonen M., Smelten N., Medart L., Pottel H., Cavalier E. Dephosphorylated-uncarboxylated Matrix Gla protein concentration is predictive of vitamin K status and is correlated with vascular calcification in a cohort of hemodialysis patients. BMC Nephrol. 2014;15:145. doi: 10.1186/1471-2369-15-145.
    1. Delanaye P., Dubois B.E., Lukas P., Peters P., Krzesinski J.M., Pottel H., Cavalier E. Impact of stopping vitamin K antagonist therapy on concentrations of dephospho-uncarboxylated Matrix Gla protein. Clin. Chem. Lab. Med. 2015;53:e191–e193. doi: 10.1515/cclm-2015-0073.
    1. Fewtrell M.S., Benden C., Williams J.E., Chomtho S., Ginty F., Nigdikar S.V., Jaffe A. Undercarboxylated osteocalcin and bone mass in 8-12 year old children with cystic fibrosis. J. Cyst. Fibros. 2008;7:307–312. doi: 10.1016/j.jcf.2007.11.006.
    1. Gundberg C.M., Nieman S.D., Abrams S., Rosen H. Vitamin K status and bone health: An analysis of methods for determination of undercarboxylated osteocalcin. J. Clin. Endocrinol. Metab. 1998;83:3258–3266. doi: 10.1210/jc.83.9.3258.
    1. Greenspan S.L., Resnick N.M., Parker R.A. Early changes in biochemical markers of bone turnover are associated with long-term changes in bone mineral density in elderly women on alendronate, hormone replacement therapy, or combination therapy: A three-year, double-blind, placebo-controlled, randomized clinical trial. J. Clin. Endocrinol. Metab. 2005;90:2762–2767. doi: 10.1210/jc.2004-1091.
    1. Rosen C.J., Chesnut C.H., III, Mallinak N.J. The predictive value of biochemical markers of bone turnover for bone mineral density in early postmenopausal women treated with hormone replacement or calcium supplementation. J. Clin. Endocrinol. Metab. 1997;82:1904–1910. doi: 10.1210/jcem.82.6.4004.
    1. Lee W., Chung H.J., Kim S., Jang S., Park C.J., Chi H.S., Chun S., Min W.K. PIVKA-II is a candidate marker for monitoring the effects of the oral anticoagulant warfarin. Clin. Biochem. 2010;43:1177–1179. doi: 10.1016/j.clinbiochem.2010.06.022.
    1. Bügel S. Vitamin K and bone health in adult humans. Vitam. Horm. 2008;78:393–416. doi: 10.1016/S0083-6729(07)00016-7.
    1. Shea M.K., Loeser R.F., Hsu F.C., Booth S.L., Nevitt M., Simonsick E.M., Strotmeyer E.S., Vermeer C., Kritchevsky S.B. Vitamin K status and lower extremity function in older adults: The Health Aging and Body Composition Study. J. Gerontol. A Biol. Sci. Med. Sci. 2016;71:1348–1355. doi: 10.1093/gerona/glv209.
    1. Shea M.K., Kritchevsky S.B., Loeser R.F., Booth S.L. Vitamin K status and mobility limitation and disability in older adults: The Health, Aging, and Body Composition Study. J. Gerontol. A Biol. Sci. Med. Sci. 2019:glz108. doi: 10.1093/gerona/glz108.
    1. Machado-Fragua M.D., Hoogendijk E.O., Struijk E.A., Rodriguez-Artalejo F., Lopez-Garcia E., Beulens J.W., van Ballegooijen A.J. High dephospho-uncarboxylated matrix Gla protein concentrations, a plasma biomarker of vitamin K, in relation to frailty: The Longitudinal Aging Study Amsterdam. Eur. J. Nutr. 2019 doi: 10.1007/s00394-019-01984-9.
    1. Price C.T., Langford J.R., Liporace F.A. Essential nutrients for bone health and a review of their availability in the average North American diet. Open Orthop. J. 2012;6:143–149. doi: 10.2174/1874325001206010143.
    1. Feskanich D., Weber P., Willett W.C., Rockett H., Booth S.L., Colditz G.A. Vitamin K intake and hip fractures in women: A prospective study. Am. J. Clin. Nutr. 1999;69:74–79. doi: 10.1093/ajcn/69.1.74.
    1. Shiraki M., Shiraki Y., Aoki C., Miura M. Vitamin K2 (menatetrenone) effectively prevents fractures and sustains lumbar bone mineral density in osteoporosis. J. Bone Miner. Res. 2000;15:515–521. doi: 10.1359/jbmr.2000.15.3.515.
    1. Iwamoto J. Vitamin K2 therapy for postmenopausal osteoporosis. Nutrients. 2014;6:1971–1980. doi: 10.3390/nu6051971.
    1. Iwamoto J., Takeda T., Sato Y. Menatetrenone (Vitamin K2) and bone quality in the treatment of postmenopausal osteoporosis. Nutr. Rev. 2006;64:509–517. doi: 10.1111/j.1753-4887.2006.tb00184.x.
    1. Rejnmark L., Vestergaard P., Charles P., Hermann A.P., Brot C., Eiken P., Mosekilde L. No effect of vitamin K1 intake on bone mineral density and fracture risk in perimenopausal women. Osteoporos. Int. 2006;17:1122–1132. doi: 10.1007/s00198-005-0044-3.
    1. Apalset E.M., Gjesdal C.G., Eide G.E., Tell G.S. Intake of vitamin K1 and K2 and risk of hip fractures: The Hordaland Health Study. Bone. 2011;49:990–995. doi: 10.1016/j.bone.2011.07.035.
    1. Schurgers L.J., Teunissen K.J., Hamulyák K., Knapen M.H., Vik H., Vermeer C. Vitamin K-containing dietary supplements: Comparison of synthetic vitamin K1 and natto-derived menaquinone-7. Blood. 2007;109:3279–3283. doi: 10.1182/blood-2006-08-040709.
    1. Iwamoto J., Takeda T., Ichimura S. Effect of combined administration of vitamin D3 and vitamin K2 on bone mineral density of the lumbar spine in postmenopausal women with osteoporosis. J. Orthop. Sci. 2000;5:546–551. doi: 10.1007/s007760070003.
    1. Iwamoto J., Takeda T., Ichimura S. Effect of menatetrenone on bone mineral density and incidence of vertebral fractures in postmenopausal women with osteoporosis: A comparison with the effect of etidronate. J. Orthop. Sci. 2001;6:487–492. doi: 10.1007/s007760100002.
    1. Ishida Y., Kawai S. Comparative efficacy of hormone replacement therapy, etidronate, calcitonin, alfacalcidol, and vitamin K in postmenopausal women with osteoporosis: The Yamaguchi Osteoporosis Prevention Study. Am. J. Med. 2004;117:549–555. doi: 10.1016/j.amjmed.2004.05.019.
    1. Orimo H., Shiraki M., Tomita A., Morii H., Fujita T., Ohata M. Effects of menatetrenone on the bone and calcium metabolism in osteoporosis: A double-blind placebo-controlled study. J. Bone Miner. Metab. 1998;16:106–112. doi: 10.1007/s007740050034.
    1. Inoue T., Fujita T., Kishimoto H., Makino T., Nakamura T., Nakamura T., Sato T., Yamazaki K. Randomized controlled study on the prevention of osteoporotic fractures (OF Study): A phase IV clinical study of 15-mg menatetrenone capsules. J. Bone Miner. Metab. 2009;27:66–75. doi: 10.1007/s00774-008-0008-8.
    1. Huang Z.B., Wan S.L., Lu Y.J., Ning L., Liu C., Fan S.W. Does vitamin K2 play a role in the prevention and treatment of osteoporosis for postmenopausal women: A meta-analysis of randomized controlled trials. Osteoporos. Int. 2015;26:1175–1186. doi: 10.1007/s00198-014-2989-6.
    1. Mott A., Bradley T., Wright K., Cockayne E.S., Shearer M.J., Adamson J., Lanham-New S.A., Torgerson D.J. Effect of vitamin K on bone mineral density and fractures in adults: An updated systematic review and meta-analysis of randomised controlled trials. Osteoporos. Int. 2019;30:1543–1559. doi: 10.1007/s00198-019-04949-0.
    1. Palermo A., Tuccinardi D., D’Onofrio L., Watanabe M., Maggi D., Maurizi A.R., Greto V., Buzzetti R., Napoli N., Pozzilli P., et al. Vitamin K and osteoporosis: Myth or reality? Metabolism. 2017;70:57–71. doi: 10.1016/j.metabol.2017.01.032.
    1. Tanaka S., Miyazaki T., Uemura Y., Kuroda T., Miyakawa N., Nakamura T., Fukunaga M., Ohashi Y., Ohta H., Mori S., et al. Comparison of concurrent treatment with vitamin K2 and risedronate compared with treatment with risedronate alone in patients with osteoporosis: Japanese Osteoporosis Intervention Trial-03. J. Bone Miner. Metab. 2017;35:385–395. doi: 10.1007/s00774-016-0768-5.
    1. Giri T.K., Newton D., Chaudhary O., Deych E., Napoli N., Villareal R., Diemer K., Milligan P.E., Gage F.B. Maximal dose-response of vitamin-K2 (menaquinone-4) on undercarboxylated osteocalcin in women with osteoporosis. Int. J. Vitam. Nutr. Res. 2019:1–7. doi: 10.1024/0300-9831/a000554.
    1. Neogi T., Booth S.L., Zhang Y.Q., Jacques P.F., Terkeltaub R., Aliabadi P., Felson D.T. Low vitamin K status is associated with osteoarthritis in the hand and knee. Arthritis Rheum. 2006;54:1255–1261. doi: 10.1002/art.21735.
    1. Oka H., Akune T., Muraki S., En-yo Y., Yoshida M., Saika A., Sasaki S., Nakamura K., Kawaguchi H., Yoshimura N. Association of low dietary vitamin K intake with radiographic knee osteoarthritis in the Japanese elderly population: Dietary survey in a population-based cohort of the ROAD study. J. Orthop. Sci. 2009;14:687–692. doi: 10.1007/s00776-009-1395-y.
    1. Houston D.K., Tooze J.A., Neiberg R.H., Hausman D.B., Johnson M.A., Cauley J.A., Bauer D.C., Cawthon P.M., Shea M.K., Schwartz G.G., et al. 25-Hydroxyvitamin D status and change in physical performance and strength in older adults: The Health, Aging, and Body Composition Study. Am. J. Epidemiol. 2012;176:1025–1034. doi: 10.1093/aje/kws147.
    1. Naito K., Watari T., Obayashi O., Katsube S., Nagaoka I., Kaneko K. Relationship between serum undercarboxylated osteocalcin and hyaluronan levels in patients with bilateral knee osteoarthritis. Int. J. Mol. Med. 2012;29:756–760. doi: 10.3892/ijmm.2012.897.
    1. Wallin R., Schurgers L.J., Loeser R.F. Biosynthesis of the vitamin K-dependent matrix Gla protein (MGP) in chondrocytes: A fetuin-MGP protein complex is assembled in vesicles shed from normal but not from osteoarthritic chondrocytes. Osteoarthr. Cartil. 2010;18:1096–1103. doi: 10.1016/j.joca.2010.05.013.
    1. Silaghi C., Fodor D., Cristea V., Crãciun A.M. Synovial and serum levels of uncarboxylated matrix Gla-protein (ucMGP) in patients with arthritis. Clin. Chem. Lab. Med. 2012;50:125–128. doi: 10.1515/cclm.2011.713.
    1. Neogi T., Felson D.T., Sarno R., Booth S.L. Vitamin K in hand osteoarthritis: Results from a randomised clinical trial. Ann. Rheum Dis. 2008;67:1570–1573. doi: 10.1136/ard.2008.094771.
    1. Shishavan N.G., Gargari B.P., Jafarabadi M.A., Kolahi S., Haggifar S., Noroozi S. Vitamin K1 supplementation did not alter inflammatory markers and clinical status in patients with rheumatoid arthritis. Int. J. Vitam. Nutr. Res. 2019:1–7. doi: 10.1024/0300-9831/a000276.
    1. Greene M.A., Loeser R.F. Aging-related inflammation in osteoarthritis. Osteoarthr. Cartil. 2015;23:1966–1971. doi: 10.1016/j.joca.2015.01.008.
    1. Rosenthal A.K. Crystals, inflammation, and osteoarthritis. Curr. Opin. Rheumatol. 2011:170–173. doi: 10.1097/BOR.0b013e3283432d1f.
    1. Liu Y.Z., Jackson A.P., Cosgrove S.D. Contribution of calcium-containing crystals to cartilage degradation and synovial inflammation in osteoarthritis. Osteoarthr. Cartil. 2009;17:1333–1340. doi: 10.1016/j.joca.2009.04.022.
    1. Rafael M.S., Cavaco S., Viegas C.S.B., Santos S., Ramos A., Willems B., Herfs M., Theuwissen E., Vermeer C., Simes D.C. Insights into the association of Gla-rich protein and osteoarthritis, novel splice variants and γ carboxylation status. Mol. Nutr. Food Res. 2014;58:1636–1646. doi: 10.1002/mnfr.201300941.
    1. Cavaco S., Viegas C.S., Rafael M.S., Ramos A., Magalhães J., Blanco F.J., Vermeer C., Simes D.C. Gla-rich protein is involved in the cross-talk between calcification and inflammation in osteoarthritis. Cell. Mol. Life Sci. 2016;73:1051–1065. doi: 10.1007/s00018-015-2033-9.
    1. Ebina K., Shi K., Hirao M., Kaneshiro S., Morimoto T., Koizumi K., Yoshikawa H., Hashimoto J. Vitamin K2 administration is associated with decreased disease activity in patients with rheumatoid arthritis. Mod. Rheumatol. 2013;23:1001–1007. doi: 10.3109/s10165-012-0789-4.
    1. Abdel-Rahman M.S., Alkady E.A.M., Ahmed S. Menaquinone-7 as a novel pharmacological therapy in the treatment of rheumatoid arthritis: A clinical study. Eur. J. Pharmacol. 2015;761:273–278. doi: 10.1016/j.ejphar.2015.06.014.
    1. Ohsaki Y., Shirakawa H., Hiwatashi K., Furukawa Y., Mizutani T., Komai M. Vitamin K suppresses lipopolysaccharide-induced inflammation in the rat. Biosci. Biotechnol. Biochem. 2006;70:926–932. doi: 10.1271/bbb.70.926.
    1. Reddi K., Henderson B., Meghji S., Wilson M., Poole S., Hopper C., Harris M., Hodges S.J. Interleukin 6 production by lipopolysaccharide-stimulated human fibroblasts is potently inhibited by naphthoquinone (vitamin K) compounds. Cytokine. 1995;7:287–290. doi: 10.1006/cyto.1995.0034.
    1. Beulens J.W., Bots M.L., Atsma F., Bartelink M.L., Prokop M., Geleijnse J.M., Witteman J.C., Grobbee D.E., van der Schouw Y.T. High dietary menaquinone intake is associated with reduced coronary calcification. Atherosclerosis. 2009:489–493. doi: 10.1016/j.atherosclerosis.2008.07.010.
    1. Geleijnse J.M., Vermeer C., Grobbee D.E., Schurgers L.J., Knapen M.H., van der Meer I.M., Hofman A., Witteman J.C. Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: The Rotterdam Study. J. Nutr. 2004;134:3100–3105. doi: 10.1093/jn/134.11.3100.
    1. Gast G.C., de Roos N.M., Sluijs I., Bots M.L., Beulens J.W., Geleijnse J.M., Witteman J.C., Grobbee D.E., Peeters P.H., van der Schouw Y.T. A high menaquinone intake reduces the incidence of coronary heart disease. Nutr. Metab. Cardiovasc. Dis. 2009;19:504–510. doi: 10.1016/j.numecd.2008.10.004.
    1. van Ballegooijen A.J., Beulens J.W. The role of Vitamin K status in cardiovascular health: Evidence from observational and clinical studies. Curr. Nutr. Rep. 2017;6:197–205. doi: 10.1007/s13668-017-0208-8.
    1. Barrett H., O’Keeffe M., Kavanagh E., Walsh M., O’Connor E.M. Is matrix Gla protein associated with vascular calcification? A systematic review. Nutrients. 2018;10:415. doi: 10.3390/nu10040415.
    1. Puzantian H., Akers S.R., Oldland G., Javaid K., Miller R., Ge Y., Ansari B., Lee J., Suri A., Hasmath Z., et al. Circulating dephospho-uncarboxylated matrix Gla-protein is associated with kidney dysfunction and arterial stiffness. Am. J. Hypertens. 2018;31:988–994. doi: 10.1093/ajh/hpy079.
    1. Liabeuf S., Bourron O., Olivier B., Vemeer C., Theuwissen E., Magdeleyns E., Aubert C.E., Brazier M., Mentaverri R., Hartemann A., et al. Vascular calcification in patients with type 2 diabetes: The involvement of matrix Gla protein. Cardiovasc. Diabetol. 2014;13:85. doi: 10.1186/1475-2840-13-85.
    1. Schurgers L.J., Joosen I.A., Laufer E.M., Chatrou M.L.L., Herfs M., Winkens M.H.M., Westenfeld R., Veulemans V., Krueger T., Shanahan C.M., et al. Vitamin K-antagonists accelerate atherosclerotic calcification and induce a vulnerable plaque phenotype. PLoS ONE. 2012;7:e43229. doi: 10.1371/journal.pone.0043229.
    1. Seidlerová J., Wohlfahrt P., Filipovský J., Vaněk J., Cífková R., Windrichová J., Topolčan O., Knapen M.H., Drummen N.E., Vermeer C., et al. Desphospho-uncarboxylated matrix Gla protein is associated with increased aortic stiffness in a general population. J. Hum. Hypertens. 2015;30:418–423. doi: 10.1038/jhh.2015.55.
    1. Pivin E., Ponte B., Pruijm M., Ackermann D., Guessous I., Ehret G., Liu Y.P., Drummen N.E., Knapen M.H., Pechere-Bertschi A., et al. Inactive Matrix Gla-Protein Is associated with arterial stiffness in an adult population-based study. Hypertension. 2015;66:85–92. doi: 10.1161/HYPERTENSIONAHA.115.05177.
    1. van den Heuvel E.M., van Schoor N.M., Lips P., Magdeleyns E.P., Deeg D.H., Vermeer C., den Heijer M. Circulating uncarboxylated matrix Gla protein, a marker of vitamin K status, as a risk factor of cardiovascular disease. Maturitas. 2014;77:137–141. doi: 10.1016/j.maturitas.2013.10.008.
    1. Shea M.K., O’Donnell C.J., Vermeer C., Magdeleyns E.P., Crosier M.D., Gundberg C.M., Ordovas J.M., Kritchevsky S.B., Booth S.L. Circulating uncarboxylated matrix gla protein is associated with vitamin K nutritional status, but not coronary artery calcium, in older adults. J. Nutr. 2011;141:1529–1534. doi: 10.3945/jn.111.139634.
    1. Dalmeijer G.W., van der Schouw Y.T., Magdeleyns E.J., Vermeer C., Verschuren W.M.M., Boer J.M., Beulens J.W.J. Circulating desphospho-uncarboxylated matrix γ-carboxyglutamate protein and the risk of coronary heart disease and stroke. J. Thromb. Haemost. 2014;12:1028–1034. doi: 10.1111/jth.12609.
    1. Dalmeijer G.W., van der Schouw Y.T., Booth S.L., de Jong P.A., Beulens J.J. Phylloquinone concentrations and the risk of vascular calcification in healthy women. Arterioscler. Thromb. Vasc. Biol. 2014;34:1587–1590. doi: 10.1161/ATVBAHA.114.303853.
    1. Knapen M., Braam L., Drummen N., Bekers O., Hoeks A.G., Vermeer C. Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women. Thromb. Haemost. 2015;113:1135–1144. doi: 10.1160/TH14-08-0675.
    1. Holden R.M., Morton A.R., Garland J.S., Pavlov A., Day A.G., Booth S.L. Vitamins K and D status in stages 3-5 chronic kidney disease. Clin. J. Am. Soc. Nephrol. 2010;5:590–597. doi: 10.2215/CJN.06420909.
    1. Aoun M., Makki M., Azar H., Matta H., Chelala D.N. High dephosphorylated-uncarboxylated MGP in hemodialysis patients: Risk factors and response to vitamin K2, a pre-post intervention clinical trial. BMC Nephrol. 2017;18:191. doi: 10.1186/s12882-017-0609-3.
    1. Krueger T., Schlieper G., Schurgers L., Cornelis T., Cozzolino M., Jacobi J., Jadoul M., Ketteler M., Rump L.C., Stenvinkel P., et al. Vitamin K1 to slow vascular calcification in haemodialysis patients (VitaVasK trial): A rationale and study protocol. Nephrol. Dial. Transpl. 2014;29:1633–1638. doi: 10.1093/ndt/gft459.
    1. Vossen L.M., Schurgers L.J., van Varik B.J., Kietselaer B.L., Vermeer C., Meeder J.G., Rahel B.M., van Cauteren Y.J., Hoffland G.A., Rennenberg R.J., et al. Menaquinone supplementation to reduce vascular calcification in patients with coronaryartery disease: rationale and study protocol (VitaK-CAC Trial) Nutrients. 2015;7:8905–8915. doi: 10.3390/nu7115443.
    1. Lindholt J.S., Frandsen N.E., Fredgart M.H., Øvrehus K.A., Dahl J.S., Møller J.E., Folkestad L., Urbonaviciene G., Becker S.W., Lambrechtsen J., et al. Effects of menaquinone-7 supplementation in patients with aortic valve calcification: Study protocol for a randomised controlled trial. BMJ Open. 2018;8:e022019. doi: 10.1136/bmjopen-2018-022019.
    1. Silva A.P., Viegas C.S., Simes D.C., Mendes F., Tavares N., Rato F., Santos N., Neves P.L. Gla-Rich Protein as a novel marker for calcifications in diabetic patients with CKD. Nephrol. Dial. Transpl. 2018;33:i493. doi: 10.1093/ndt/gfy104.SP430.
    1. Viegas C.S., Santos L., Macedo A.L., Matos A.A., Silva A.P., Neves P.L., Staes A., Gevaert K., Morais R., Vermeer C., et al. Chronic kidney disease circulating calciprotein particles and extracellular vesicles promote vascular calcification: A role for GRP (Gla-rich protein) Arterioscler. Thromb. Vasc. Biol. 2018;38:575–587. doi: 10.1161/ATVBAHA.117.310578.
    1. Franceschi C., Bonafè M., Valensin S., Olivieri F., De Luca M., Ottaviani E., De Benedictis G. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann. N. Y. Acad. Sci. 2000;908:244–254. doi: 10.1111/j.1749-6632.2000.tb06651.x.
    1. Franceschi C., Garagnani P., Vitale G., Capri M., Salvioli S. Inflammaging and ‘garb-aging’. Trends Endocrinol. Metab. 2017;28:199–212. doi: 10.1016/j.tem.2016.09.005.
    1. Muñoz-Espín D., Serrano M. Cellular senescence: From physiology to pathology. Nat. Rev. Mol. Cell. Biol. 2014;15:482–496. doi: 10.1038/nrm3823.
    1. Ferrucci L., Fabbri E. Inflammageing: Chronic inflammation in ageing, cardiovascular disease, and frailty. Nat. Rev. Cardiol. 2018;15:505–522. doi: 10.1038/s41569-018-0064-2.
    1. Rezuș E., Cardoneanu A., Burlui A., Luca A., Codreanu C., Tamba B.I., Stanciu G.D., Dima N., Bădescu C., Rezuș C. The link between inflammaging and degenerative joint diseases. Int. J. Mol. Sci. 2019;20:614. doi: 10.3390/ijms20030614.
    1. Ruparelia N., Chai J.T., Fisher E.A., Choudhury R.P. Inflammatory processes in cardiovascular disease: A route to targeted therapies. Nat. Rev. Cardiol. 2017;14:133–144. doi: 10.1038/nrcardio.2016.185.
    1. Preston C.C., Oberlin A.S., Holmuhamedov E.L., Gupta A., Sagar S., Syed R.H., Siddiqui S.A., Raghavakaimal S., Terzic A., Jahangir A. Aging-induced alterations in gene transcripts and functional activity of mitochondrial oxidative phosphorylation complexes in the heart. Mech. Ageing Dev. 2008;129:304–312. doi: 10.1016/j.mad.2008.02.010.
    1. Short K.R., Bigelow M.L., Kahl J., Singh R., Coenen-Schimke J., Raghavakaimal S., Nair K.S. Decline in skeletal muscle mitochondrial function with aging in humans. Proc. Natl. Acad. Sci. USA. 2005;102:5618–5623. doi: 10.1073/pnas.0501559102.
    1. López-Armada M.J., Riveiro-Naveira R.R., Vaamonde-García C., Valcárcel-Ares M.N. Mitochondrial dysfunction and the inflammatory response. Mitochondrion. 2013;13:106–118. doi: 10.1016/j.mito.2013.01.003.
    1. Theurey P., Pizzo P. The Aging Mitochondria. Genes. 2018;9:22. doi: 10.3390/genes9010022.
    1. Vos M., Esposito G., Edirisinghe J.N., Vilain S., Haddad D.M., Slabbaert J.R., Van Meensel S., Schaap O., De Strooper B., Meganathan R., et al. Vitamin K2 is a mitochondrial electron carrier that rescues pink1 deficiency. Science. 2012;336:1306–1310. doi: 10.1126/science.1218632.
    1. Hwang H.S., Kim H.A. Chondrocyte apoptosis in the pathogenesis of osteoarthritis. Int. J. Mol. Sci. 2015;16:26035–26054. doi: 10.3390/ijms161125943.
    1. Hashimoto S., Ochs R.L., Rosen F., Quach J., McCabe G., Solan J., Seegmiller J.E., Terkeltaub R., Lotz M. Chondrocyte-derived apoptotic bodies and calcification of articular cartilage. Proc. Natl. Acad. Sci. USA. 1998;95:3094–3099. doi: 10.1073/pnas.95.6.3094.
    1. Kim H.A., Suh D.I., Song Y.W. Relationship between chondrocyte apoptosis and matrix depletion in human articular cartilage. J. Rheumatol. 2001;28:2038–2045.
    1. Proudfoot D., Skepper J.N., Hegyi L., Bennett M.R., Shanahan C.M., Weissberg P.L. Apoptosis regulates human vascular calcification in vitro: Evidence for initiation of vascular calcification by apoptotic bodies. Circ. Res. 2000;87:1055–1062. doi: 10.1161/01.RES.87.11.1055.
    1. Giachelli C.M. Ectopic calcification: Gathering hard facts about soft tissue mineralization. Am. J. Pathol. 1999;154:671–675. doi: 10.1016/S0002-9440(10)65313-8.
    1. O’Donnell K., Harkes I.C., Dougherty L., Wicks I.P. Expression of receptor tyrosine kinase Axl and its ligand Gas6 in rheumatoid arthritis: Evidence for a novel endothelial cell survival pathway. Am. J. Pathol. 1999;154:1171–1180. doi: 10.1016/S0002-9440(10)65369-2.
    1. Healy A.M., Schwartz J.J., Zhu X., Herrick B.E., Varnum B., Farber H.W. Gas 6 promotes Axl-mediated survival in pulmonary endothelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 2001;280:L1273–L1281. doi: 10.1152/ajplung.2001.280.6.L1273.
    1. D’Arcangelo D., Gaetano C., Capogrossi M.C. Acidification prevents endothelial cell apoptosis by Axl activation. Circ. Res. 2002;91:e4–e12. doi: 10.1161/01.RES.0000036753.50601.E9.
    1. Hasanbasic I., Rajotte I., Blostein M. The role of gamma-carboxylation in the anti-apoptotic function of gas6. J. Thromb. Haemost. 2005;3:2790–2797. doi: 10.1111/j.1538-7836.2005.01662.x.
    1. Melaragno M.G., Cavet M.E., Yan C., Tai L.K., Jin Z.G., Haendeler J., Berk B.C. Gas6 inhibits apoptosis in vascular smooth muscle: Role of Axl kinase and Akt. J. Mol. Cell. Cardiol. 2004;37:881–887. doi: 10.1016/j.yjmcc.2004.06.018.
    1. Qiu C., Cheng H., Tao H., Yu W., Jiang X., Li A., Jin H., Lv A., Li H. Vitamin K2 inhibits rat vascular smooth muscle cell calcification by restoring the Gas6/Axl/Akt anti-apoptotic pathway. Mol. Cell. Biochem. 2017;433:149–159. doi: 10.1007/s11010-017-3023-z.
    1. Shea M.K., Dallal G.E., Dawson-Hughes B., Ordovas J.M., O’Donnell C.J., Gundberg C.M., Peterson J.W., Booth S.L. Vitamin K, circulating cytokines, and bone mineral density in older men and women. Am. J. Clin. Nutr. 2008;88:356–363. doi: 10.1093/ajcn/88.2.356.
    1. Shea M.K., Cushman M., Booth S.L., Burke G.L., Chen H., Kritchevsky S.B. Associations between vitamin K status and haemostatic and inflammatory biomarkers in community-dwelling adults. Thromb. Haemost. 2014;112:438–444. doi: 10.1160/TH13-12-1003.
    1. Viegas C.S., Costa R.M., Santos L., Videira P.A., Silva Z., Araújo N., Macedo A.L., Matos A.P., Vermeer C., Simes D.C. Gla-rich protein function as an anti-inflammatory agent in monocytes/macrophages: Implications for calcification-related chronic inflammatory diseases. PLoS ONE. 2017;12:e0177829. doi: 10.1371/journal.pone.0177829.
    1. van Ballegooijen A.J., van Putten S.R., Visser M., Beulens J.W., Hoogendijk E.O. Vitamin K status and physical decline in older adults-The Longitudinal Aging Study Amsterdam. Maturitas. 2018;113:73–79. doi: 10.1016/j.maturitas.2018.04.013.
    1. Shea M.K., Booth S.L., Miller M.E., Burke G.L., Chen H., Cushman M., Tracy R.P., Kritchevsky S.B. Association between circulating vitamin K1 and coronary calcium progression in community-dwelling adults: The Multi-Ethnic Study of Atherosclerosis. Am. J. Clin. Nutr. 2013;98:197–208. doi: 10.3945/ajcn.112.056101.
    1. Stepanova M., Rodriguez E., Birerdinc A., Baranova A. Age-independent rise of inflammatory scores may contribute to accelerated aging in multi-morbidity. Oncotarget. 2015;6:1414–1421. doi: 10.18632/oncotarget.2725.
    1. Walston J., McBurnie M.A., Newman A., Tracy R.P., Kop W.J., Hirsch C.H., Gottdiener J., Fried L.P. Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: Results from the Cardiovascular Health Study. Arch. Intern. Med. 2002;162:2333–2341. doi: 10.1001/archinte.162.20.2333.
    1. Hubbard R.E., O’Mahony M.S., Savva G.M., Calver B.L., Woodhouse K.W. Inflammation and frailty measures in older people. J. Cell. Mol. Med. 2009;13:3103–3109. doi: 10.1111/j.1582-4934.2009.00733.x.
    1. Wang J., Maxwell C.A., Yu F. Biological processes and biomarkers related to frailty in older adults: a state-of-the-science literature review. Biol. Res. Nurs. 2019;21:80–106. doi: 10.1177/1099800418798047.
    1. Hubbard R.E., Woodhouse K.W. Frailty, inflammation and the elderly. Biogerontology. 2010;11:635–641. doi: 10.1007/s10522-010-9292-5.
    1. Li J., Lin J.C., Wang H., Peterson J.W., Furie B.C., Furie B., Booth S.L., Volpe J.J., Rosenberg P.A. Novel role of vitamin k in preventing oxidative injury to developing oligodendrocytes and neurons. J. Neurosci. 2003;23:5816–5826. doi: 10.1523/JNEUROSCI.23-13-05816.2003.
    1. Westhofen P., Watzka M., Marinova M., Hass M., Kirfel G., Müller J., Bevans C.G., Müller C.R., Oldenburg J. Human vitamin K 2,3-epoxide reductase complex subunit 1-like 1 (VKORC1L1) mediates vitamin K-dependent intracellular antioxidant function. J. Biol. Chem. 2011;286:15085–15094. doi: 10.1074/jbc.M110.210971.
    1. Mukai K., Itoh S., Morimoto H.J. Stopped-flow kinetic study of vitamin E regeneration reaction with biological hydroquinones(reduced forms of ubiquinone, vitamin K, and tocopherol quinone) in solution. Biol. Chem. 1992;267:22277–22281.
    1. Vervoort L.M., Ronden J.E., Thijssen H.H. The potent antioxidant activity of the vitamin K cycle in microsomal lipid peroxidation. Biochem. Pharmacol. 1997;54:871–876. doi: 10.1016/S0006-2952(97)00254-2.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner