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Thromb Haemost 2009; 101(02): 359-366
DOI: 10.1160/TH08-04-0241
Cardiovascular Biology and Cell Signalling
Schattauer GmbH

Uncarboxylated matrix Gla protein (ucMGP) is associated with coronary artery calcification in haemodialysis patients

Ellen C. M. Cranenburg   *
1   VitaK and Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
,
Vincent M. Brandenburg   *
2   Department of Nephrology and Clinical Immunology, RWTH University Hospital Aachen, Germany
,
Cees Vermeer
1   VitaK and Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
,
Melanie Stenger
2   Department of Nephrology and Clinical Immunology, RWTH University Hospital Aachen, Germany
,
Georg Mühlenbruch
3   Department of Diagnostic Radiology, RWTH University Hospital Aachen, Germany
,
Andreas H. Mahnken
3   Department of Diagnostic Radiology, RWTH University Hospital Aachen, Germany
,
Ulrich Gladziwa
4   Department of Internal Medicine, University of Witten/Herdecke, Germany
,
Markus Ketteler
2   Department of Nephrology and Clinical Immunology, RWTH University Hospital Aachen, Germany
,
Leon J. Schurgers
1   VitaK and Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
› InstitutsangabenFinancial support: This work was supported by a grant from GENZYME.
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Publikationsverlauf

Received: 18. April 2008

Accepted after major revision: 11. Januar 2008

Publikationsdatum:
23. November 2017 (online)

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Summary

Matrix γ-carboxyglutamate (Gla) protein (MGP) is a potent local inhibitor of cardiovascular calcification and accumulates at areas of calcification in its uncarboxylated form (ucMGP). We previously found significantly lower circulating ucMGP levels in patients with a high vascular calcification burden. Here we report on the potential of circulating ucMGP to serve as a biomarker for vascular calcification in haemodialysis (HD) patients. Circulating ucMGP levels were measured with an ELISA-based assay in 40 HD patients who underwent multi-slice computed tomography (MSCT) scanning to quantify the extent of coronary artery calcification (CAC). The mean ucMGP level in HD patients (193 ± 65 nM) was significantly lower as compared to apparently healthy subjects of the same age (441 ± 97 nM; p < 0.001) and patients with rheumatoid arthritis (RA) without CAC (560 ± 140 nM; p < 0.001). Additionally, ucMGP levels correlated inversely with CAC scores (r = –0.41; p = 0.009), and this correlation persisted after adjustment for age, dialysis vintage and high-sensitivity C-reactive protein (hs-CRP). Since circulating ucMGP levels are significantly and inversely correlated with the extent of CAC in HD patients, ucMGP may become a tool for identifying HD patients with a high probability of cardiovascular calcification.

Keywords

Calcification - dialysis - Gla-domain proteins - matrix Gla protein - vitamin K

* The first two authors have contributed equally to this work.


 

  • References

  • 1 US Renal Data System.. USRDS 1998 annual data report. Bethesda: National Institute of Diabetes and Kidney Diseases; 1999: 63-90.
    Google Scholar
  • 2 US Renal Data System.. USRDS 1998 annual data report. Bethesda: National Institute of Diabetes and Kidney Diseases; 1999: 79-90.
    Google Scholar
  • 3 Shanahan CM, Cary NR, Salisbury JR. et al. Medial localization of mineralization-regulating proteins in association with Monckeberg’s sclerosis: evidence for smooth muscle cell-mediated vascular calcification. Circulation 1999; 100: 2168-2176.
    CrossrefPubMedGoogle Scholar
  • 4 Lehto S, Niskanen L, Suhonen M. et al. Medial artery calcification. A neglected harbinger of cardiovascular complications in non-insulin-dependent diabetes mellitus. Arterioscler Thromb Vasc Biol 1996; 16: 978-983.
    CrossrefPubMedGoogle Scholar
  • 5 Blacher J, Guerin AP, Pannier B. et al. Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension 2001; 38: 938-942.
    CrossrefPubMedGoogle Scholar
  • 6 London GM, Guerin AP, Marchais SJ. et al. Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant 2003; 18: 1731-1740.
    CrossrefPubMedGoogle Scholar
  • 7 London GM, Marchais SJ, Guerin AP. et al. Arterial structure and function in end-stage renal disease. Nephrol Dial Transplant 2002; 17: 1713-1724.
    CrossrefPubMedGoogle Scholar
  • 8 Guerin AP, London GM, Marchais SJ. et al. Arterial stiffening and vascular calcifications in end-stage renal disease. Nephrol Dial Transplant 2000; 15: 1014-1021.
    CrossrefPubMedGoogle Scholar
  • 9 Raggi P, Boulay A, Chasan-Taber S. et al. Cardiac calcification in adult hemodialysis patients. A link between end-stage renal disease and cardiovascular disease? J Am Coll Cardiol 2002; 39: 695-701.
    PubMedGoogle Scholar
  • 10 McCullough PA, Sandberg KR, Dumler F. et al. Determinants of coronary vascular calcification in patients with chronic kidney disease and end-stage renal disease: a systematic review. J Nephrol 2004; 17: 205-215.
    PubMedGoogle Scholar
  • 11 Luo G, D’Souza R, Hogue D. et al. The matrix Gla protein gene is a marker of the chondrogenesis cell lineage during mouse development. J Bone Miner Res 1995; 10: 325-334.
    PubMedGoogle Scholar
  • 12 Wallin R, Cain D, Sane DC. Matrix Gla protein synthesis and gamma-carboxylation in the aortic vessel wall and proliferating vascular smooth muscle cells--a cell system which resembles the system in bone cells. Thromb Haemost 1999; 82: 1764-1767.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 13 El-Maadawy S, Kaartinen MT, Schinke T. et al. Cartilage formation and calcification in arteries of mice lacking matrix Gla protein. Connect Tissue Res 2003; 44: 272-278.
    CrossrefPubMedGoogle Scholar
  • 14 Vermeer C. Gamma-carboxyglutamate-containing proteins and the vitamin K-dependent carboxylase. Biochem J 1990; 266: 625-636.
    CrossrefPubMedGoogle Scholar
  • 15 Schurgers LJ, Cranenburg ECM, Vermeer C. Matrix Gla-protein: The calcification inhibitor in need of vitamin K. Thromb Haemost 2008; 100: 593-603.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 16 Cranenburg EC, Schurgers LJ, Vermeer C. Vitamin K: The coagulation vitamin that became omnipotent. Thromb Haemost 2007; 98: 120-125.
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 17 Cranenburg EC, Vermeer C, Koos R. et al. The circulating inactive form of Matrix Gla Protein (ucMGP) as a biomarker for cardiovascular calcification. J Vasc Res 2008; 45: 427-436.
    CrossrefPubMedGoogle Scholar
  • 18 Jie KS, Bots ML, Vermeer C. et al. Vitamin K intake and osteocalcin levels in women with and without aortic atherosclerosis: a population-based study. Atherosclerosis 1995; 116: 117-123.
    CrossrefPubMedGoogle Scholar
  • 19 Geleijnse JM, Vermeer C, Grobbee DE. 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.
    CrossrefPubMedGoogle Scholar
  • 20 Luo G, Ducy P, McKee MD. et al. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature 1997; 386: 78-81.
    CrossrefPubMedGoogle Scholar
  • 21 Murshed M, Schinke T, McKee MD. et al. Extracellular matrix mineralization is regulated locally; different roles of two gla-containing proteins. J Cell Biol 2004; 165: 625-630.
    CrossrefPubMedGoogle Scholar
  • 22 Schurgers LJ, Teunissen KJ, Knapen MH. et al. Novel conformation-specific antibodies against matrix gamma-carboxyglutamic acid (Gla) protein: undercarboxylated matrix Gla protein as marker for vascular calcification. Arterioscler Thromb Vasc Biol 2005; 25: 1629-1633.
    CrossrefPubMedGoogle Scholar
  • 23 Robinson J, Tan AU, Wilensky RL. et al. Electron-beam computerized tomography correlates with coronary angiogram in chronic kidney disease patients. Am J Nephrol 2007; 27: 247-252.
    CrossrefPubMedGoogle Scholar
  • 24 Block GA, Raggi P, Bellasi A. et al. Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients. Kidney Int 2007; 71: 438-441.
    CrossrefPubMedGoogle Scholar
  • 25 Hermans MM, Vermeer C, Kooman JP. et al. Undercarboxylated matrix GLA protein levels are decreased in dialysis patients and related to parameters of calcium-phosphate metabolism and aortic augmentation index. Blood Purif 2007; 25: 395-401.
    CrossrefPubMedGoogle Scholar
  • 26 Hermans MM, Brandenburg V, Ketteler M. et al. Study on the relationship of serum fetuin-A concentration with aortic stiffness in patients on dialysis. Nephrol Dial Transplant 2006; 21: 1293-1299.
    CrossrefPubMedGoogle Scholar
  • 27 Mahnken AH, Wildberger JE, Sinha AM. et al. Variation of the coronary calcium score depending on image reconstruction interval and scoring algorithm. Invest Radiol 2002; 37: 496-502.
    CrossrefPubMedGoogle Scholar
  • 28 Agatston AS, Janowitz WR, Hildner FJ. et al. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990; 15: 827-832.
    CrossrefPubMedGoogle Scholar
  • 29 Rumberger JA, Brundage BH, Rader DJ. et al. Electron beam computed tomographic coronary calcium scanning: a review and guidelines for use in asymptomatic persons. Mayo Clin Proc 1999; 74: 243-252.
    CrossrefPubMedGoogle Scholar
  • 30 Goodman WG, Goldin J, Kuizon BD. et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 2000; 342: 1478-1483.
    CrossrefPubMedGoogle Scholar
  • 31 Newman AB, Naydeck BL, Sutton-Tyrrell K. et al. Coronary artery calcification in older adults to age 99: prevalence and risk factors. Circulation 2001; 104: 2679-2684.
    CrossrefPubMedGoogle Scholar
  • 32 Barrett-Connor E, Laughlin GA, Connor C. Coronary artery calcium versus intima-media thickness as a measure of cardiovascular disease among asymptomatic adults (from the Rancho Bernardo Study). Am J Cardiol 2007; 99: 227-231.
    CrossrefPubMedGoogle Scholar
  • 33 Fair JM, Kiazand A, Varady A. et al. Ethnic differences in coronary artery calcium in a healthy cohort aged 60 to 69 years. Am J Cardiol 2007; 100: 981-985.
    CrossrefPubMedGoogle Scholar
  • 34 Price PA, Faus SA, Williamson MK. Warfarin-induced artery calcification is accelerated by growth and vitamin D. Arterioscler Thromb Vasc Biol 2000; 20: 317-327.
    CrossrefPubMedGoogle Scholar
  • 35 Sweatt A, Sane DC, Hutson SM. et al. Matrix Gla protein (MGP) and bone morphogenetic protein-2 in aortic calcified lesions of aging rats. J Thromb Haemost 2003; 1: 178-185.
    CrossrefPubMedGoogle Scholar
  • 36 Price PA, Faus SA, Williamson MK. Warfarin causes rapid calcification of the elastic lamellae in rat arteries and heart valves. Arterioscler Thromb Vasc Biol 1998; 18: 1400-1407.
    CrossrefPubMedGoogle Scholar
  • 37 Schurgers LJ, Spronk HMH, Skepper JN. et al. Post-translational modifications regulate matrix Gla protein function: importance for inhibition of vascular smooth muscle cell calcification. J Thromb Haemost 2007; 5: 2503-2511.
    CrossrefPubMedGoogle Scholar
  • 38 Reynolds JL, Joannides AJ, Skepper JN. et al. Human vascular smooth muscle cells undergo vesicle-mediated calcification in response to changes in extra-cellular calcium and phosphate concentrations: a potential mechanism for accelerated vascular calcification in ESRD. J Am Soc Nephrol 2004; 15: 2857-2867.
    CrossrefPubMedGoogle Scholar
  • 39 Shroff RC, Shah V, Hiorns MP. et al. The circulating calcification inhibitors, fetuin-A and osteoprotegerin, but not Matrix Gla protein, are associated with vascular stiffness and calcification in children on dialysis. Nephrol Dial Transplant 2008; 23: 3263-3272.
    CrossrefPubMedGoogle Scholar