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Table of Contents
ORIGINAL ARTICLE
Year : 2018  |  Volume : 7  |  Issue : 3  |  Page : 144-147

Could Biglycan be a biomarker of coronary artery disease? A pilot human study


1 Department of Clinical Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
2 Department of Research and Education, Razavi Hospital, Mashhad, Iran
3 Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad; Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Al Zahra, Karbala, Iran
4 Department of Anatomy; Department of Cardiology, Birjand Cardiovascular Disease Research Center, Birjand University of Medical Sciences, Birjand, Iran
5 Department of Clinical Pharmacy, School of Pharmacy; Pharmaceutical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

Date of Web Publication10-Sep-2018

Correspondence Address:
Dr. Amir Hooshang Mohammadpour
P. O. Box 91775-1365, Mashhad
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/rcm.rcm_23_18

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  Abstract 


Background: Coronary artery calcification (CAC) is utilized as an important tool for the global risk assessment of cardiovascular events in individuals with intermediate risk. Biglycan (BGN) is a small leucine-rich proteoglycan that induces the calcification of arterial smooth muscle cell. This study aimed to evaluate the correlation between BGN serum concentration and CAC in human for the first time. Patients and Methods: Eighty-four patients with coronary artery disease (CAD) were included in the study. A questionnaire consisting of demographic data and traditional cardiovascular risk factors was completed for all patients. patients did not complete the questionnaire, it was completed by the pharmacy student. CAC score and BGN serum concentrations were determined using computed tomography angiography and enzyme-linked immunosorbent assay method, respectively. Results: There was no significant correlation between BGN serum concentration and total CAC score and also CAC of different branches of coronary artery (P > 0.05). Conclusion: On the basis of our results, BGN serum concentration is not a suitable biomarker of CAD. Studies with a higher sample size are necessary for its confirmation.

Keywords: Biglycan, biomarker, coronary artery calcification, glycosaminoglycan, proteoglycans, tumor necrosis factor-β


How to cite this article:
Rezapour A, Moradian M, Nazemi S, Moallem SA, Issazadeh S, Elyasi S, Afshar M, Baghshani Z, Zaerzadeh A, Mohammadpour AH. Could Biglycan be a biomarker of coronary artery disease? A pilot human study. Res Cardiovasc Med 2018;7:144-7

How to cite this URL:
Rezapour A, Moradian M, Nazemi S, Moallem SA, Issazadeh S, Elyasi S, Afshar M, Baghshani Z, Zaerzadeh A, Mohammadpour AH. Could Biglycan be a biomarker of coronary artery disease? A pilot human study. Res Cardiovasc Med [serial online] 2018 [cited 2018 Dec 17];7:144-7. Available from: http://www.rcvmonline.com/text.asp?2018/7/3/144/240991




  Introduction Top


Vascular calcification is a life-threatening complication of cardiovascular disease and is an independent risk factor for high morbidity and mortality.[1] Vascular calcification is an important feature of atherosclerosis and cardiovascular diseases, and it is an inevitable process, particularly in the advanced stages of atherosclerosis, which can create a break in the vessels and cause the plaque rupture. Coronary artery calcification (CAC) is a surrogate marker for subclinical atherosclerosis, and it is known to reflect the atherosclerotic burden. Increased coronary artery calcium score (CACS) correlates with the risk of future cardiovascular disease.[2] CAC was determined by electron-beam computed tomography (EBCT). EBCT was recently determined as a strong predictor that comforts the prediction of future cardiovascular events, particularly in intermediate-risk patients, while in the past, CAC has been proposed as a poor prognostic factor for vascular disease.[3]

Recent studies have provided impetus to shift from cellular interaction-based calcification models to models emphasizing on the important role of extracellular matrix (ECM) in calcification. The ECM contains a number of noncollagenous matrix molecules such as proteoglycans, which are important regulators of bone mineralization, as they regulate collagen fibril formation and directly control hydroxyapatite crystal growth.[4] The proteoglycans are the ingredient of superfamily leucine-rich repeat (>300 members).[5] They consist of one or more glycosaminoglycan (GAG) side chains bound to a core protein. According to the type of the GAG, the proteoglycans is classified into dermatan sulfate, heparan sulfate, keratan sulfate, and chondroitin sulfate proteoglycans.[6],[7] Biglycan (BGN) consists of a 42-kDa core protein covalently bound to two chondroitin sulfate/dermatan sulfate side chains.[8] BGN is synthesized by arterial smooth muscle cells, and transforming growth factor (TGF-β1) increases BGN mRNA synthesis.[9],[10] Proteoglycans, especially those belonging to the small leucine-rich proteoglycan family which BGN is an exponent example, have a significant role in calcification. The study of in vitro and in vivo animal models suggests an important role of BGN in arterial calcification.[11] Oxidized low-density lipoprotein (Ox-LDL) which induces vascular smooth muscle cell calcification [12] promotes BGN expression in vascular smooth muscle cells. BGN also mediates the deposition of ox-LDL and regulates the pro-osteogenic effects of it on calcification.[11],[13] Ox-LDL increases bone morphogenetic protein-2 (BMP-2) expression in human coronary artery endothelial cells through a mechanism related to toll-like receptor-2 (TLR2) and TLR4. Since soluble BGN stimulates the expression of BMP-2 and alkaline phosphatase (ALP) on calcification through interaction with TLR2/4 and the activation of the extracellular signal-regulated kinase-1/2 (ERK1/2) pathway, it is probable that BGN plays an important role in the adjustment of the pro-osteogenic effects of ox-LDL.[11],[14]

According to these data, we evaluated the BGN as a diagnostic biomarker in human to determine the extent of vascular calcification and subsequent coronary disorders such as CAC. It should be mentioned that to the best of our knowledge, it was the first human study in this field.


  Patients and Methods Top


Patients

Eighty-four patients with diagnosis of coronary artery disease (CAD) were enrolled in this study between November 2015 and March 2016. Patients were recruited from the Cardiology Ward of Razavi Hospital, Mashhad, Iran. This study was approved by the Ethics Committee of Mashhad University of Medical Sciences (code: 931459). Patients with calcium and phosphor metabolic disorder, parathyroid disease, renal dysfunction, history of osteoarticular disorders, and zero calcium score were excluded from the study. A questionnaire containing demographic data, laboratory data, drug history, medical history, and familial history of cardiovascular risk factors was completed by all patients. All patients signed consent form before entering into the study.

Determination of biglycan serum concentration and coronary artery calcification

Whole blood was collected from patients and was centrifuged at 2500 rpm for 10 min. The plasma fraction was isolated and stored at −70°C until required for analysis. Routine biochemical measurements such as plasma glucose, total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and serum calcium and phosphorus levels were carried out using routine laboratory methods. Serum level of soluble BGN was measured with an enzyme-linked immunosorbent assay kit (Zellbio, Germany); each assay was calibrated using BGN standard curve following the manufacturer's instructions. CAC was determined by CT-angiography.

Statistical analysis

Statistical analysis was carried out using SPSS 16 statistical package (SPSS Inc., USA), and all measured values are presented as mean ± standard deviation. The correlation between serum concentration of BGN and CAC was analyzed using the Spearman's correlation test. To compare the serum concentration of BGN between different groups, independent-sample t-test was used. The results were considered statistically significant at P < 0.05.


  Results Top


Characteristics of the study population

The study population consists of 84 patients: male (77%) and female (23%). The mean age of the population was 56.80 ± 10.73 years. Patients' characteristics and laboratory tests including biochemical parameters, traditional cardiovascular risk factors, and mean decorin serum level are summarized in [Table 1].
Table 1: Patients' characteristic, laboratory data, traditional cardiovascular risk factors, and mean decorin serum level of patients

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Correlation between biglycan serum level and coronary artery calcification Agatston score

There was no significant correlation between BGN serum level and total CAC score and also CAC score of the left anterior descending artery (LAD), left main coronary artery (LMCA), right coronary artery (RCA), and circumflex (CX) (P > 0.05) [Table 2].
Table 2: Correlation between biglycan serum concentration with left anterior descending, right coronary artery, left main coronary artery, and circumflex coronary artery calcification score

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  Discussion Top


In this study, the correlation of the BGN serum level with CAC was evaluated in patients with CAD. As can be found from the aforementioned results, there was no significant correlation between BGN serum level and total CAC and CAC of RCA, LAD, LM, and CX (P ≥ 0.05). Until now, the relationship between the BGN serum concentration and CAC has been investigated in vitro or only in animal models. In accordance with the obtained results from the previous studies, it is entirely apparent that the BGN stimulates calcification by means of osteogenic mediators' induction.

The expression of BGN is promoted by ox-LDL. BGN is an inner activator of TLRs, especially TLR2 and TLR4 that are involved in the activity of nuclear factor-kB, ERK1/2, and P38 mitogen-activated protein kinase pathways.[15],[16] The studies indicate that BGN can increase the expression of BMP-2 and TGF-β1 in human vascular calcification through innate immune receptors by differentiation of the osteoblast cells. The aforesaid factors induce osteogenic response in interstitial cells of arteries.[11],[17] In another study, BGN's role in the expression of pro-osteogenic biomarkers, such as ALP, osteopontin, osterix, bone sialoprotein, and Runx 2 and consequently calcium settlement in vessels, was shown.[11],[18]

According to the results mentioned above, there was no significant relationship between the CAC and BGN serum concentration.

It is possible that by increasing the studied population size – as there are enough data about calcium score in different subgroups – we can understand the relationship between this biomarker and CAC much better. On the other hand, the CACS of the studied patients in the subgroups was not distributed uniformly. Perhaps if the calcium score distribution was balanced, a significant relationship could be found.


  Conclusion Top


In this study, the correlation of the BGN serum level with CAC was clinically evaluated for the first time that there was no statistically significant correlation between BGN serum level and total CAC and CAC of RCA, LAD, LM, and CX (P ≥ 0.05).

Acknowledgment

This study is part of a research thesis for a Ph.D. at Mashhad University of Medical Sciences.

Financial support and sponsorship

This study was financially supported by Mashhad University of Medical Sciences.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Santos RD, Nasir K, Carvalho JA, Raggi P, Blumenthal RS. Coronary calcification and coronary heart disease death rates in different countries, not only the influence of classical risk factors. Atherosclerosis 2009;202:32-3.  Back to cited text no. 1
    
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Abedin M, Tintut Y, Demer LL. Vascular calcification: Mechanisms and clinical ramifications. Arterioscler Thromb Vasc Biol 2004;24:1161-70.  Back to cited text no. 2
    
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Budoff MJ, Achenbach S, Blumenthal RS, Carr JJ, Goldin JG, Greenland P, et al. Assessment of coronary artery disease by cardiac computed tomography: A scientific statement from the American Heart Association Committee on Cardiovascular Imaging and Intervention, Council on Cardiovascular Radiology and Intervention, and Committee on Cardiac Imaging, Council on Clinical Cardiology. Circulation 2006;114:1761-91.  Back to cited text no. 3
    
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Gorski JP. Acidic phosphoproteins from bone matrix: A structural rationalization of their role in biomineralization. Calcif Tissue Int 1992;50:391-6.  Back to cited text no. 4
    
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Hultgårdh-Nilsson A, Borén J, Chakravarti S. The small leucine-rich repeat proteoglycans in tissue repair and atherosclerosis. J Intern Med 2015;278:447-61.  Back to cited text no. 5
    
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Iozzo RV. Matrix proteoglycans: From molecular design to cellular function. Annu Rev Biochem 1998;67:609-52.  Back to cited text no. 6
    
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Shimizu-Hirota R, Sasamura H, Kuroda M, Kobayashi E, Hayashi M, Saruta T, et al. Extracellular matrix glycoprotein biglycan enhances vascular smooth muscle cell proliferation and migration. Circ Res 2004;94:1067-74.  Back to cited text no. 7
    
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Fisher LW, Termine JD, Young MF. Deduced protein sequence of bone small proteoglycan I (biglycan) shows homology with proteoglycan II (decorin) and several nonconnective tissue proteins in a variety of species. J Biol Chem 1989;264:4571-6.  Back to cited text no. 8
    
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Järveläinen HT, Kinsella MG, Wight TN, Sandell LJ. Differential expression of small chondroitin/dermatan sulfate proteoglycans, PG-I/biglycan and PG-II/decorin, by vascular smooth muscle and endothelial cells in culture. J Biol Chem 1991;266:23274-81.  Back to cited text no. 9
    
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O'Brien KD, Olin KL, Alpers CE, Chiu W, Ferguson M, Hudkins K, et al. Comparison of apolipoprotein and proteoglycan deposits in human coronary atherosclerotic plaques: Colocalization of biglycan with apolipoproteins. Circulation 1998;98:519-27.  Back to cited text no. 10
    
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Song R, Zeng Q, Ao L, Yu JA, Cleveland JC, Zhao KS, et al. Biglycan induces the expression of osteogenic factors in human aortic valve interstitial cells via toll-like receptor-2. Arterioscler Thromb Vasc Biol 2012;32:2711-20.  Back to cited text no. 11
    
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Yan J, Stringer SE, Hamilton A, Charlton-Menys V, Götting C, Müller B, et al. Decorin GAG synthesis and TGF-β signaling mediate ox-LDL-induced mineralization of human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 2011;31:608-15.  Back to cited text no. 12
    
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Chang MY, Potter-Perigo S, Tsoi C, Chait A, Wight TN. Oxidized low density lipoproteins regulate synthesis of monkey aortic smooth muscle cell proteoglycans that have enhanced native low density lipoprotein binding properties. J Biol Chem 2000;275:4766-73.  Back to cited text no. 13
    
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Su X, Ao L, Shi Y, Johnson TR, Fullerton DA, Meng X, et al. Oxidized low density lipoprotein induces bone morphogenetic protein-2 in coronary artery endothelial cells via toll-like receptors 2 and 4. J Biol Chem 2011;286:12213-20.  Back to cited text no. 14
    
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Babelova A, Moreth K, Tsalastra-Greul W, Zeng-Brouwers J, Eickelberg O, Young MF, et al. Biglycan, a danger signal that activates the NLRP3 inflammasome via toll-like and P2X receptors. J Biol Chem 2009;284:24035-48.  Back to cited text no. 15
    
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Schaefer L, Babelova A, Kiss E, Hausser HJ, Baliova M, Krzyzankova M, et al. The matrix component biglycan is proinflammatory and signals through toll-like receptors 4 and 2 in macrophages. J Clin Invest 2005;115:2223-33.  Back to cited text no. 16
    
17.
Song R, Fullerton DA, Ao L, Zheng D, Zhao KS, Meng X, et al. BMP-2 and TGF-β1 mediate biglycan-induced pro-osteogenic reprogramming in aortic valve interstitial cells. J Mol Med (Berl) 2015;93:403-12.  Back to cited text no. 17
    
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Parisuthiman D, Mochida Y, Duarte WR, Yamauchi M. Biglycan modulates osteoblast differentiation and matrix mineralization. J Bone Miner Res 2005;20:1878-86.  Back to cited text no. 18
    



 
 
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