Could BMP-2 and BMP-7 be biomarkers of coronary artery disease? A pilot clinical study

Saeed Nazemi; Atefeh Rezapour; Seyed Mohammad Hasan Moallem; Mohammad Afshar; Sepideh Elyasi; Elham Hashemi; Sheyda Golmohammadzadeh; Azadeh Zaerzadeh; Vahid Jomezadeh; Amir Hooshang Mohammadpour

doi:10.1016/j.artres.2018.05.006

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Volume 23, Issue C, September 2018, Pages 14 - 19

Could BMP-2 and BMP-7 be biomarkers of coronary artery disease? A pilot clinical study

Authors

Saeed Nazemi^a, Atefeh Rezapour^b, Seyed Mohammad Hasan Moallem^c, Mohammad Afshar^d^{, e}, Sepideh Elyasi^b, Elham Hashemi^f, Sheyda Golmohammadzadeh^a, Azadeh Zaerzadeh^b, Vahid Jomezadeh^g, Amir Hooshang Mohammadpour^b^{, h}^{, *}

^aDepartment of Cardiovascular Diseases, Razavi Hospital, Mashhad, Iran

^bDepartment of Clinical Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

^cFaculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

^dDepartment of Anatomy, Birjand University of Medical Sciences, Birjand, Iran

^eMedical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

^fBirjand Cardiovascular Disease Research Center, Department of Cardiology, Birjand University of Medical Sciences, Birjand, Iran

^gDepartment of Surgery, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

^hPharmaceutical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

^*Corresponding author. P.O. Box 91775-1365, Mashhad, Iran. Fax: +985138823251. E-mail address: MohamadpoorAH@mums.ac.ir (A.H. Mohammadpour).

Corresponding Author

Amir Hooshang Mohammadpour

Received 31 December 2017, Revised 8 May 2018, Accepted 14 May 2018, Available Online 29 May 2018.

DOI: 10.1016/j.artres.2018.05.006 How to use a DOI?
Keywords: Coronary artery calcification; BMP-2 – BMP-7; SMAD signaling pathway; TGF-β
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. BMP-2 is a powerful inducer of bone formation and exposure to BMP-2 in the arteries leads to the loss of vascular smooth muscle cells (VSMC) markers and increase gene expression in favor of osteoblasts. BMP-7 is key factor in the bone and kidney and is suggested as inhibitor of vascular calcification. The main purpose of this clinical study was to find out the correlation between BMP-2 and BMP-7serum concentration and CAC in human for the first time.

Methods: In this study 84 patients with coronary artery disease who fulfilled inclusion and exclusion criteria, entered the study. For all patients a questionnaire consisting demographic data and traditional cardiovascular risk factors were completed. CT-Angiography was carried out to determine coronary artery calcium score and ELISA method was used for measuring BMP-2 and BMP-7serum concentrations.

Results: There was a significant positive correlation between BMP-2 serum concentration and total CAC score and also CAC of right coronary artery (RCA), left anterior descending (LAD), circumflex (CX), left main coronary artery (LMCA) (P < 0.05). Similar result was found for BMP-7 serum concentration except in LMCA (P > 0.05).

Conclusion: Based on our results, we can suggest BMP-2 and BMP-7 serum concentration as a probable biomarker for coronary artery disease. However, more studies with higher sample size are necessary for its confirmation.
Copyright: © 2018 Association for Research into Arterial Structure and Physiology. Published by Elsevier B.V. All rights reserved.
Open Access: This is an open access article distributed under the CC BY-NC license.

Introduction

Vascular calcification is a life threatening complication of cardiovascular disease and the statistics of patients with vascular calcification, especially in the elderly people and people with metabolic disorders, are on the rise. This process not only leads to increased mortality, but also leads to physical disabilities and a decrease in the quality of life.^1,2 It is an inevitable process particularly in the advanced stages of atherosclerosis which can create break in the vessels and cause the plaque rupture. Coronary artery calcification (CAC) is a surrogate marker for subclinical atherosclerosis and is known to reflect atherosclerotic burden. Increased coronary artery calcium score (CACS) correlates with the risk of cardiovascular disease.³ CAC determined by electron beam-computed tomography (EBCT). EBCT was recently determined as strong predictor that comforts the prediction of future cardiovascular events particularly in intermediate risk subjects.⁴

Recent studies have provided impetus to shift from cellular interaction based calcification models to models emphasizing on the important role of extracellular matrix in calcification.

The bone mineralization controlling proteins are also involved in vascular calcification.⁵ Bone morphogenic proteins (BMPs) are proteins associated with growth factors and subset of TGF-β superfamily. These proteins, along with the angiogenesis-inducing factors and through the paracrine-endothelial-mesenchymal pathway, maintain bone structure.⁶ BMPs signaling path is so powerful in bone formation that its induction in the muscle tissue leads to the formation of false bone tissue in the place.⁷ BMPs are expressed by endothelial cells, smooth muscle cells and foamy cells in atherosclerotic vascular areas.⁸ Among the proteins in this family, BMP-2 and BMP4 And at a later stage BMP 5, 6, 7 have the highest association with vascular disease due to calcification.⁸

BMP-2 is a powerful inducer of bone formation and exposure to BMP-2 in the arteries leading to the loss of vascular smooth muscle cells (VSMC) markers and increase gene expression in favor of osteoblasts.⁸

Different molecular pathways have been reported for BMP-2 that SMAD pathway is the most important one. Actually, two SMAD dependent and non-SMAD dependent mechanism pathways are available that both of them trigger calcification process by induction of Osx, Runx2, and Dlx5 transcription.⁹

The second molecular pathway that is listed for BMP-2 stimulates Msx2 gene expression through induction of ALP and Runx2/Cbfa1 track progress to increases in favor of bone formation.^2,8,10

BMP-7 is key factor in the bone and kidney, and genetically modified mice with a defect in BMP-7, have bone disorders and hypo-mineralization patterns, renal dysplasia and kidney growth inhibition, and visual defects.⁸

BMP-7 and its derivatives by stimulating phosphate storage by increasing smad6, smad7 and p₂₁ Using the SMAD signaling pathway in the skeletal system lead to reduce plasma phosphate levels, which play a major role in vascular calcification and inhibits it and also induce the VSMC phenotype.^8,11

According to this, we evaluated the BMP-2 and BMP-7 as diagnostic biomarkers in human to determine the extent of coronary artery calcification.

Methods

Patients

Eighty-three patients with diagnosis of coronary artery disease by angiography which was performed by the cardiologist, who aged higher than 40 years old, were enrolled in this study between November 2015 and March 2016. This test is the best way to detect CAD in the arteries, over 51% of which are blocked by atherosclerotic plaques and useful in detecting the vessels responsible for advanced CHD. However, it does not provide information about the artery wall and atherosclerosis may not be diagnosed that has not yet captured the duct. 12 patients with >50% coronary stenosis of at least one artery were considered as CAD+ and included in study. Patients with calcium and phosphor metabolic disorder or receiving medications which are effective on calcium and/or phosphate and immunosuppressant or antioxidant medications, intake of folic acid and methotrexate, malignancies, heart failure, hypo or hyper parathyroidisim, renal insufficiency, history of osteoarticular disorders and chronic inflammatory diseases, and acute infection during the study were excluded from the study. A questionnaire containing demographic data, laboratory data, drug and medical and familial history of cardiovascular risk factors was completed for all patients.

Patients were recruited from Cardiology ward of Razavi Hospital, Mashhad, Iran. This study was accepted by ethics committee of Mashhad University of Medical Sciences (code of BMP-2: 931413).

A questionnaire containing demographic data, laboratory data, drug, medical, and familial history of cardiovascular risk factors was completed for all patients. All patients signed the consent form prior to entry in the study.

Determination of BMP-2 and BMP-7 serum concentration and CAC

Whole blood was collected from patients and 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 (TC), triglycerides, low density lipoprotein Cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), and serum calcium and phosphorus level were carried out by routine laboratory methods. Serum level of soluble BMP-2 and BMP-7 were measured with an enzyme-linked Immunosorbant assay (ELISA) -kit (R&D, American); each assay was calibrated using BMP-2 standard curve following the manufacturer's instructions. Coronary Artery Calcification was determined by CT-Angiography. The development of a computerized tomography scanner of Electron beam computerized tomography (EBCT) in the early 1980s made it possible to track the calcification of coronary arteries with a quality and non-invasive approach. These imaging techniques often use the Agatston scoring system based on the area and density of calcification, to evaluate the quality of coronary artery calcification. The diagnostic accuracy is high in these methods, with a sensitivity of 90–94%, a 95–97% attribute and a negative predictive value of 93–99% to detect coronary artery occlusion that is 50% or more in angiography.¹²

Statistical analysis

Statistical analysis was carried out by SPSS 19, All measured values are presented as mean ± SD. Kolmogorov–Smirnov test was used to assess the normality of the variables distributions. Correlation between serum concentrations of BMP-2 and BMP-7 with CAC was analyzed using spearman correlation test (as their distribution was non-normal). To compare serum concentration of BMP-2 and BMP-7 between different groups, Independent-sample T Test was used. Results were considered significant at p < 0.05.

Results

Characteristics of the study population

The study population consists of 84 patients, 55 male (65.5%) and 29 female (34.5%). The mean age of population was 57.19 ± 10.18 years. Patients’ characteristics, laboratory tests including biochemical parameters, and traditional cardiovascular risk factors are summarized in Table 1.

Demographic data	Mean ± SD

Age (year) (mean ± SD)	57.2 ± 10.2^a (37–89)^b
BMI (kg/m^b) (mean ± SD)	28.2 ± 4.7 (19.5–40.4)
Female/male ratio (%)	35%^c

Laboratory tests	Mean ± SD

HDL-C (mg/dl) (mean ± SD)	43 ± 13 (25–121)
LDL-C (mg/dl) (mean ± SD)	92.3 ± 31.5 (42–191)
Total cholesterol (mg/dl) (mean ± SD)	164.9 ± 35.9 (109–292)
FBS (mg/dl) (mean ± SD)	105.3 ± 28 (75–257)
TG (mg/dl) (mean ± SD)	142.9 ± 53.8 (17–295)

Traditional risk factors	Frequency (%)

Hypertension (%)	48
Dyslipidemia (%)	62
Positive family history (%)	52
Diabetes (%)	19
Current Smoking (%)	34

BMI: Body Mass Index, HDL-C: High Density Lipoprotein-Cholesterol, LDL-C: Low Density Lipoprotein-Cholesterol, FBS: Fast Blood Sugar, TG: Triglyceride.

a

Mean ± SD.

b

Minimum and maximum of range.

c

Frequency percent.

Table 1

Demographic data, laboratory tests, and traditional cardiovascular risk factors of patients.

Serum concentration of BMP-2 and BMP-7 and calcium score Total, RCA, LAD, LMCA and CX are summarized in Table 2.

	Mean ± SD
Coronary artery calcium score
Total calcification of coronary vessels (agatston score) (mean ± SD)	346.6 ± 557.8^a (0–3756)^b
Calcification in coronary LAD (agatston score) (mean ± SD)	174.7 ± 287.1 (0–1610.2)
Calcification in coronary RCA (agatston score) (mean ± SD)	65.2 ± 105.6 (0–476.8)
Calcification in coronary CX (agatston score) (mean ± SD)	45.9 ± 95.1 (0–615.2)
Calcification in coronary LMCA (agatston score) (mean ± SD)	28.2 ± 103.9 (0–749.8)
BMP-21 serum level
Concentration of BMP-2 (pg/mL) (mean ± SD)	47.6 ± 30.6 (7–115.7)
Concentration of BMP-7 (pg/mL) (mean ± SD)	320.3 ± 307. (3.4–985.6)

LAD: Left Anterior Descending, RCA: Right Coronary Artery, CX: Circumflex, LMCA: Left Main Coronary Artery, BMP-2: Bone Morph genic Protein-2, BMP-7: Bone Morph genic Protein-7.

a

Mean ± SD.

b

Minimum and maximum of range.

Table 2

Serum concentration of BMP-2 and BMP-7, calcium score Total, RCA, LAD, LMCA and CX.

Correlation between BMP-2 and BMP-7 serum level and coronary artery calcification agatston score

There was a significant positive correlation between BMP-2 serum level and total coronary artery calcification score and CAC score of RCA, LMCA, CX, LAD (P < 0.05).

There was a significant positive correlation between BMP-7 serum concentration and total CAC score and CAC of RCA, LAD, CX (P < 0.05), but there was no significant correlation between BMP-7 serum concentration and CAC of LMCA (P > 0.05) (Table 3).

	LMCA	RCA	CX	LAD	Total of CAC	Parameter
BMP-2	0.049	<0.001	<0.001	<0.001	<0.001	P value
BMP-2	0.279	0.526	0.501	0.717	0.902	CC
BMP-7	0.077	<0.001	<0.001	<0.001	<0.001	P value
BMP-7	0.253	0.587	0.485	0.753	0.911	CC

CAC: Coronary Artery Calcification, LAD: Left Anterior Descending, RCA: Right Coronary Artery LMCA: Left Main Coronary Artery, CX: Circumflex.

Table 3

Correlation between BMP-2 and BMP-7 serum concentration with LAD, RCA, LMCA, and CX coronary artery calcification score.

We evaluated the correlation of BMP-2 and BMP-7 serum level with patients’ age. There was a small significant negative correlation between BMP-2 serum level and age (P = 0.049, r = −0.215) but not with BMP-7 (P > 0.05). No significant difference also was found between serum level of BMP-2 and BMP-7 in two genders (P value = 0.78 & 0.809, respectively).

Discussion

In this study, the correlation of the BMP-2 and BMP-7 serum level with CAC was evaluated for the first time in human. As can be found from aforementioned results, there was a significant positive correlation between BMP-2 and BMP-7serum level and total CAC and CAC of RCA, LAD, LMCA, CX (P < 0.05), but, there was no significant correlation between BMP-7 serum level and CAC of LMCA (P > 0.05).

Different mechanisms have been proposed for the effects of BMP-2 on vascular calcification: The most important molecular pathway is the SMAD molecular pathway. In this path, two SMAD-dependent and non-SMAD-dependent mechanisms are expressed. In the SMAD path, the BMP-2 is connected to the type 2 receptor, and this connection causes phosphorylation of the receptor type 1 and the activation of its kinase. The receptor type 1, phosphorylates R-SMAD, and phosphorylated R-SMAD is transferred to the nucleus with SMAD, where it induces the transcription of Osx, Runx, Dlx, and initiates the calcification process. In this mechanism, I-SMAD inhibits signaling by inhibiting R-SMAD phosphorylation.⁹ In a non-SMAD dependent pathway, MAPK triggers their activity by phosphorylation of mentioned genes, and these genes induce growth, differentiation and mineralization of the primary cells.⁹ The second molecular pathway is Msx2 stimulation, which increases the expression of the gene in favor of osteosynthesis, as Msx2 induces ALP.^2,8 Also by progression of the Runx2/Cbfa1 pathway and inducing osterix in mesenchymal stem cells, ultimately leads to a favorable environment for vascular calcification.⁹ In these pathways, Runx2 is required, and it has been observed that BMP-2 function is inhibited by removing Runx2 gene in mouse specimens.¹³ The other pathways mentioned for BMP-2 are as follows: BMP-2 increases apoptosis and apoptosis is one of the key stages in the development of vascular calcification.⁹ Moreover, BMP-2 by regulative increasing of Pit-1, which is sodium-dependent type 3 phosphate transporter and increases phosphate withdrawal in dose-dependent manner. As a result, BMP-2 increases the calcification induced by high dose of phosphate.¹⁴ Besides, BMP-2 by stimulating endothelial reticuloma stress, results in increasing Nox in smooth muscle of the vessels and therefore cause regulative increasing of the Runx2 and induces calcification.¹⁵ It has also been observed that BMP-2 has an unknown effect on the metabolism of cholesterol.¹⁶

There have been a lot of in vivo and in vitro studies in this field. In one of these studies, Nakagawa et al. showed that in cultivating differentiated VSMCs, BMP-2 have increased and its endogenous inhibitors reduced.¹⁷ Also in 2011, Balderman et al. stated that there is higher level of BMP-2 in coronary artery differentiated, calcified cells enhances its possible role in the process of vascular calcification.¹⁸

In two other studies, the effect of human uremic serum, which increases calcification in the arteries, has been studied on cultured cells. The effect of uremic serum on bovine VSMCs cultivation showed that its calcification effects increase BMP-2 and its signaling paths.¹⁹ This effect has been also seen on mesenchymal stem cells, so that by interrupting the BMP-2 effects by its inhibitor, the effects of calcification induction of this serum on the cultured cells are inhibited.²⁰ It was also found that BMP-7 play a role in VSMCs differentiation and control of their differentiation associated with osteoblast phenotypes.⁸

Animal studies also indicate that increasing BMP-2 accelerates intima atherosclerotic calcification.¹⁷ In experiments performed on mice, BMPs antagonists were useful for inhibition of vascular calcification and atherosclerosis.¹⁶

In another study which examined the relationship between diabetes and vascular diseases, the higher BMP-2 level was detected in patients with diabetes in comparison with general population, and BMP-2 has a significant positive correlation with coronary artery disease, type 2 diabetes, atherosclerotic plaque calcification and also has a significant negative correlation with the volume of blood flow within vessels.²¹ This study is conducted based on a comparison between diabetic and non-diabetic patients and not providing any comprehensive results about the BMP-2 predictive capability.

Hruska et al., showed that BMP-7 and derivatives by stimulating the storage of phosphates in the skeletal system reduces the amount of phosphate in plasma that plays a major role in vascular calcification, and it inhibits the direct effects the VSMCs that significantly reduces vascular calcification. So that when uremic rats were treated with BMP-7, calcification was inhibited in these animals.^8,22 As well as in atherosclerosis rat models even when the mice were treated with BMP-7 for 15 weeks, vascular calcification reduced in the same or less than the control group.²³

In a study conducted in 2008 on 18 children with chronic renal failure showed that serum concentrations of BMP-7 in patients had increased compared to control group, probably due to a protective mechanism in kidney failure. This study has not mentioned to examine the concentrations of BMP-7 in coronary artery calcification which is the subject of this study.²⁴

In general, very few clinical studies have been done on the relationship between BMPs and vascular calcification. To the best of knowledge, a comprehensive clinical study for investigation of relationship between the serum levels of two biomarkers BMP-2 and BMP-7 and coronary artery calcification was not performed in patients with chronic ischemic heart disease.

The lack of association between LMCA and serum levels of BMP-7 may be due to the small study population. The coronary artery calcium score of the studied patients in the sub-groups was not distributed uniformly. Perhaps if the calcium score distribution was balanced, a significant relationship could be found.

The results of this study as a small pilot one, can propose the relationship between serum concentrations of BMP-2 and BMP-7 and coronary artery calcification and thus these biomarkers may have the ability to predict the CAC. Actually, this study could be the basis for studies with larger sample size and more accurate assessment of these biomarkers.

Conclusion

In this study, the correlation of the BMP-2 and BMP-7 serum level with CAC was clinically evaluated for the first time in patients with coronary artery disease that there was a significant positive correlation between BMP-2 and BMP-7 serum level and total CAC and CAC of RCA, LAD, LMCA, CX (P < 0.05), but, there was no significant correlation between BMP-7 serum level CAC of LMCA (P > 0.05).

Funding

The authors are thankful for the funding of this study by the Research Council of Mashhad University of Medical Sciences.

Conflict of interest

None.

Acknowledgments

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

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Journal: Artery Research
Volume-Issue: 23 - C
Pages: 14 - 19
Publication Date: 2018/05/29
ISSN (Online): 1876-4401
ISSN (Print): 1872-9312
DOI: 10.1016/j.artres.2018.05.006 How to use a DOI?
Open Access: This is an open access article distributed under the CC BY-NC license.

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ris enw bib

TY  - JOUR
AU  - Saeed Nazemi
AU  - Atefeh Rezapour
AU  - Seyed Mohammad Hasan Moallem
AU  - Mohammad Afshar
AU  - Sepideh Elyasi
AU  - Elham Hashemi
AU  - Sheyda Golmohammadzadeh
AU  - Azadeh Zaerzadeh
AU  - Vahid Jomezadeh
AU  - Amir Hooshang Mohammadpour
PY  - 2018
DA  - 2018/05/29
TI  - Could BMP-2 and BMP-7 be biomarkers of coronary artery disease? A pilot clinical study
JO  - Artery Research
SP  - 14
EP  - 19
VL  - 23
IS  - C
SN  - 1876-4401
UR  - https://doi.org/10.1016/j.artres.2018.05.006
DO  - 10.1016/j.artres.2018.05.006
ID  - Nazemi2018
ER  -

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