Download PDF
Thromb Haemost 2004; 91(04): 790-794
DOI: 10.1160/TH03-08-0572
Cell Signaling and Vessel Remodeling
Schattauer GmbH

Matrix Gla protein is associated with coronary artery calcification as assessed by electron-beam computed tomography

Shuichi Jono
1   Department of Metabolism, Endocrinology and Molecular Medicine, Department of Cardiovascular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
,
Yuji Ikari
2   Division of Cardiology, Mitsui Memorial Hospital, Tokyo, Japan
,
Cees Vermeer
3   Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands
,
Paul Dissel
3   Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands
,
Kotaro Hasegawa
4   Division of Cardiology, Ageo Central General Hospital, Saitama, Japan
,
Atsushi Shioi
1   Department of Metabolism, Endocrinology and Molecular Medicine, Department of Cardiovascular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
,
Hiromichi Taniwaki
1   Department of Metabolism, Endocrinology and Molecular Medicine, Department of Cardiovascular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
,
Akane Kizu
1   Department of Metabolism, Endocrinology and Molecular Medicine, Department of Cardiovascular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
,
Yoshiki Nishizawa
1   Department of Metabolism, Endocrinology and Molecular Medicine, Department of Cardiovascular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
,
Shigeru Saito
5   Division of Cardiology and Catheterization Laboratories, Heart Center of Shonan Kamakura General Hospital, Kamakura, Japan
› Author AffiliationsGrant support: This work was supported in part by a grant-in-aid for Scientific Research from Japan Society for the Promotion of Science (12671121) and by grant 2001 B033 of the Netherlands Heart Foundation.
Further Information

Publication History

Received 08 August 2003

Accepted after revision 12 January 2004

Publication Date:
06 December 2017 (online)

    Permissions and Reprints

Summary

Matrix Gla protein (MGP) is an extracellular matrix protein with wide tissue distribution. It has been demonstrated that the expression of MGP is detected not only in the normal blood vessels but also calcified atherosclerotic plaques, and that MGP deficient mice develop extensive arterial calcification. MGP is thought to be a regulator of vascular calcification. A recent clinical study demonstrates the association between polymorphisms of the MGP gene and increased risk of myocardial infarction. However, there are no reports of the relationship between serum MGP levels and coronary artery calcification (CAC). We evaluated the severity of CAC using electron-beam computed tomography (EBCT), and measured serum MGP levels by enzyme-linked immunosorbent assay in 115 subjects with suspected coronary artery disease. CAC scores were correlated with traditional risk factors, such as age, gender, hypertension, diabetes, hyperlipidemia and smoking. The serum MGP levels were lower in patients with CAC than in those without CAC (p<0.001). As the severity of CAC increased, there was a significant decrease in serum MGP levels. Serum MGP levels (U/L) were 116.7 ± 20.3, 104.9 ± 19.2, 95.2 ± 15.2 and 82.2 ± 19.7, (medians 115.5, 105.0, 94.8, and 81.9) for the subjects with normal (CAC score=0), mild (CAC score=1 to 99), moderate (CAC score=100 to 400), and severe (CAC score >400) coronary calcification, respectively. We found that serum MGP levels are inversely correlated with the severity of CAC. These data suggest a possible role for MGP in the development of vascular calcification.

Keywords

Matrix Gla protein - coronary artery calcification - atherosclerosis - vitamin K-dependent factors
 

  • References

  • 1 Rumberger JA, Simons DB, Fitzpatrick LA. et al. Coronary artery calcium area by electron-beam computed tomography and coronary atherosclerotic plaque area. A histopathologic correlative study. Circulation 1995; 92: 2157-62.
    CrossrefPubMedGoogle Scholar
  • 2 Raggi P, Callister TQ, Cooil B. et al. Identification of patients at increased risk of first unheralded acute myocardial infarction by electron-beam computed tomography. Circulation 2000; 101: 850-5.
    CrossrefPubMedGoogle Scholar
  • 3 Giachelli CM. Ectopic calcification: gathering hard facts about soft tissue mineralization. Am J Pathol 1999; 154: 671-5.
    CrossrefPubMedGoogle Scholar
  • 4 Price PA, Williamson MK. Primary structure of bovine matrix Gla protein, a new vitamin K-dependent bone protein. J Biol Chem 1985; 260: 14971-5.
    PubMedGoogle Scholar
  • 5 Dhore CR, Cleutjens JP, Lutgens E. et al. Differential expression of bone matrix regulatory proteins in human atherosclerotic plaques. Arterioscler Thromb Vasc Biol 2001; 21: 1998-2003.
    CrossrefPubMedGoogle Scholar
  • 6 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
  • 7 Herrmann SM, Whatling C, Brand E. et al. Polymorphisms of the human matrix gla protein (MGP) gene, vascular calcification, and myocardial infarction. Arterioscler Thromb Vasc Biol 2000; 20: 2386-93.
    CrossrefPubMedGoogle Scholar
  • 8 Agatston AS, Janowitz WR, Hildner FJ. et al. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990; 15: 827-32.
    CrossrefPubMedGoogle Scholar
  • 9 Braam LA, Dissel P, Gijsbers BL. et al. Assay for human matrix gla protein in serum: potential applications in the cardiovascular field. Arterioscler Thromb Vasc Biol 2000; 20: 1257-61.
    CrossrefPubMedGoogle Scholar
  • 10 Friedwald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972; 18: 499-502.
    PubMedGoogle Scholar
  • 11 Engelse MA, Neele JM, Bronckers AL. et al. Vascular calcification: expression patterns of the osteoblast-specific gene core binding factor alpha-1 and the protective factor matrix gla protein in human atherogenesis. Cardiovasc Res 2001; 52: 281-9.
    CrossrefPubMedGoogle Scholar
  • 12 Zhao J, Warburton D. Matrix Gla protein gene expression is induced by transforming growth factor-beta in embryonic lung culture. Am J Physiol 1997; 273: L282-7.
    PubMedGoogle Scholar
  • 13 Fraser JD, Otawara Y, Price PA. 1,25-Dihydroxyvitamin D3 stimulates the synthesis of matrix gamma-carboxyglutamic acid protein by osteosarcoma cells. Mutually exclusive expression of vitamin K-dependent bone proteins by clonal osteoblastic cell lines. J Biol Chem 1988; 263: 911-6.
    PubMedGoogle Scholar
  • 14 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: 1764-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Mori K, Shioi A, Jono S. et al. Expression of matrix Gla protein (MGP) in an in vitro model of vascular calcification. FEBS Lett 1998; 433: 19-22.
    CrossrefPubMedGoogle Scholar
  • 16 Proudfoot D, Skepper JN, Shanahan CM. et al. Calcification of human vascular cells in vitro is correlated with high levels of matrix Gla protein and low levels of osteopontin expression. Arterioscler Thromb Vasc Biol 1998; 18: 379-88.
    CrossrefPubMedGoogle Scholar
  • 17 Farzaneh-Far A, Proudfoot D, Weissberg PL. et al. Matrix gla protein is regulated by a mechanism functionally related to the calcium-sensing receptor. Biochem Biophys Res Commun 2000; 277: 736-40.
    CrossrefPubMedGoogle Scholar
  • 18 Zebboudj AF, Imura M, Bostrom K. Matrix GLA protein, a regulatory protein for bone morphogenetic protein-2. J Biol Chem 2002; 277: 4388-94.
    CrossrefPubMedGoogle Scholar
  • 19 Cozzolino M, Dusso AS, Slatopolsky E. Role of calcium-phosphate product and bone-associated proteins on vascular calcification in renal failure. J Am Soc Nephrol 2001; 12: 2511-16.
    PubMedGoogle Scholar
  • 20 Jono S, Nishizawa Y, Shioi A. et al. Parathyroid hormone-related peptide as a local regulator of vascular calcification. Its inhibitory action on in vitro calcification by bovine vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 1997; 17: 1135-42.
    CrossrefPubMedGoogle Scholar
  • 21 Jono S, Nishizawa Y, Shioi A. et al. 1,25-Dihydroxyvitamin D3 increases in vitro vascular calcification by modulating secretion of endogenous parathyroid hormone-related peptide. Circulation 1998; 98: 1302-6.
    CrossrefPubMedGoogle Scholar
  • 22 Raggi P. The use of electron-beam computed tomography as a tool for primary prevention. Am J Cardiol 2001; 88: 28J-32J.
    PubMedGoogle Scholar
  • 23 Hale JE, Williamson MK, Price PA. Carboxylterminal proteolytic processing of matrix Gla protein. J Biol Chem 1991; 266: 21145-9.
    PubMedGoogle Scholar
  • 24 Price PA, Thomas GR, Pardini AW. et al. Discovery of a high molecular weight complex of calcium, phosphate, fetuin, and matrix gamma-carboxyglutamic acid protein in the serum of etidronate-treated rats. J Biol Chem 2002; 277: 3926-34.
    CrossrefPubMedGoogle Scholar
  • 25 Ketteler M, Bongartz P, Westenfeld R. et al. Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study. Lancet 2003; 361: 827-33.
    CrossrefPubMedGoogle Scholar
  • 26 Spronk HM, Soute BA, Schurgers LJ. et al. Matrix Gla protein accumulates at the border of regions of calcification and normal tissue in the media of the arterial vessel wall. Biochem Biophys Res Commun 2001; 289: 485-90.
    CrossrefPubMedGoogle Scholar