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

Shuichi Jono; Yuji Ikari; Cees Vermeer; Paul Dissel; Kotaro Hasegawa; Atsushi Shioi; Hiromichi Taniwaki; Akane Kizu; Yoshiki Nishizawa; Shigeru Saito

doi:10.1160/TH03-08-0572

Thrombosis and Haemostasis, Table of Contents

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

¹Department of Metabolism, Endocrinology and Molecular Medicine, Department of Cardiovascular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan

,

Yuji Ikari

²Division of Cardiology, Mitsui Memorial Hospital, Tokyo, Japan

,

Cees Vermeer

³Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands

,

Paul Dissel

³Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands

,

Kotaro Hasegawa

⁴Division of Cardiology, Ageo Central General Hospital, Saitama, Japan

,

Atsushi Shioi

¹Department of Metabolism, Endocrinology and Molecular Medicine, Department of Cardiovascular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan

,

Hiromichi Taniwaki

¹Department of Metabolism, Endocrinology and Molecular Medicine, Department of Cardiovascular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan

,

Akane Kizu

¹Department of Metabolism, Endocrinology and Molecular Medicine, Department of Cardiovascular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan

,

Yoshiki Nishizawa

¹Department of Metabolism, Endocrinology and Molecular Medicine, Department of Cardiovascular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan

,

Shigeru Saito

⁵Division of Cardiology and Catheterization Laboratories, Heart Center of Shonan Kamakura General Hospital, Kamakura, Japan

› Author Affiliations

Abstract

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

Full Text

References

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.
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.
3 Giachelli CM. Ectopic calcification: gathering hard facts about soft tissue mineralization. Am J Pathol 1999; 154: 671-5.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
22 Raggi P. The use of electron-beam computed tomography as a tool for primary prevention. Am J Cardiol 2001; 88: 28J-32J.
23 Hale JE, Williamson MK, Price PA. Carboxylterminal proteolytic processing of matrix Gla protein. J Biol Chem 1991; 266: 21145-9.
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.
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.
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.