| Abstract|| |
Background: Secreted frizzled-related protein 5 (SFRP5) is an anti-inflammatory adipokine that excreted by adipose tissue and functions to modulate metabolic and inflammatory dysregulations. The exact contribution of SFRP5 toward coronary artery disease (CAD) is largely unclear. Objectives: In the current study, the potential role of SFRP5, by particular focusing on its anti-inflammatory effects, was sought in CAD. Patients and Methods: Serum levels of SFRP5 and the inflammatory biomarkers, oxidized low-density lipoprotein (Ox-LDL), and high-sensitivity C-reactive protein (hsCRP), were measured in 40 CAD patients and 40 controls who were identified based on coronary angiography examinations. The status of CAD severity (in accord with Gensini score) and traditional CAD risk factors were also determined. Association of SFRP5 with Ox-LDL, hsCRP, CAD severity, and traditional CAD risk factors was analyzed. Results: Serum SFRP5 level in CAD patients was significantly decreased compared to controls (28.60 ng/mL [25.67–34.58] vs. 39.92 ng/mL [32.82-49.91], P = 0.000). The correlation of serum SFRP5 level with hsCRP, Ox-LDL, body mass index, and Gensini score was reveal to be significant and negative (P < 0.05). Serum SFRP5 level was independently and inversely associated with CAD (odds ratio, 0.28 [95% confidence interval, 0.11–0.56], P = 0.001) and differentiated between CAD patients and controls (P = 0.01). Conclusions: Decreased level of serum SFRP5 is associated with CAD, highlighting its implication in CAD. It may also be a clinically useful biomarker for CAD.
Keywords: Adipokine, biomarkers, coronary artery disease
|How to cite this article:|
Gharibi A, Yaghmaei P, Basati G, Soleimannejad K, Abbasi N. Decreased level of the anti-inflammatory adipokine, secreted frizzled-related protein 5, in patients with coronary artery disease. Ann Trop Med Public Health 2017;10:1735-9
|How to cite this URL:|
Gharibi A, Yaghmaei P, Basati G, Soleimannejad K, Abbasi N. Decreased level of the anti-inflammatory adipokine, secreted frizzled-related protein 5, in patients with coronary artery disease. Ann Trop Med Public Health [serial online] 2017 [cited 2018 Nov 17];10:1735-9. Available from: http://www.atmph.org/text.asp?2017/10/6/1735/222709
| Introduction|| |
Secreted frizzled-related protein 5 (SFRP5), a recently known antagonist of noncanonical wnt5a signaling, is secreted by adipose tissue and protects against metabolic dysregulation and inflammation. Given that the atherosclerosis is a low-grade inflammatory disorder in nature, SFRP5 has been suspected as a novel effector of adipose tissue linked chronic inflammatory comorbidities such as cardiovascular diseases. The reduced SFRP5 state may promote Wnt5a signaling in favor of chronic inflammatory condition that occur in cardiovascular disorders. It should be regarded that Wnt5a provokes inflammation in endothelial cells  and is expressed in atherosclerotic lesions of mouse and human. Therefore, by taking into account the counteracting effects of SFRP5 on noncanonical Wnt5a signaling, the cardioprotective action of SFRP5 might be conceivable.
Studies focusing on the circulating levels of SFRP5 in coronary artery disease (CAD) are limited. In a study in individuals with and without CAD, Miyoshi et al. found that low serum SFRP5 levels were independently associated with CAD. Moreover, lower plasma SFRP5 levels have also been reported in individuals with obesity and type 2 diabetes,, the underlying conditions predisposing to CAD.
To provide further evidence regarding the exact role of serum SFRP5 levels in CAD, with emphasizing its anti-inflammatory impacts, we determined the serum levels of SFRP5 in a relatively large number of CAD patients compared to their control counterparts.
| Patients and Methods|| |
The individuals enrolled in the case–control study consisted of 40 CAD patients and 40 controls who consecutively underwent coronary angiography examination for treatment purposes at the Shahid Mostafa Khomeini Hospital in Ilam from January 2015 to July 2016. All angiograms were assessed by two independent cardiologists who unaware from the patient's specifications. The main diagnostic criterion for selecting patients and controls were coronary artery stenosis ≥50% and <50%, respectively, on angiography examination. Gensini scoring system was used to assess the severity of atherosclerotic plaques in the diseased coronary arteries. In this system, the scores 1, 2, 4, 8, 16, and 32, are dedicated to the coronary artery stenosis percentages 25%, 50%, 75%, 90%, 99%, and 100%, respectively. Each score then is multiplied by a factor which represented the importance and location of the involved coronary artery segment and ranged from 0.5 to 5 as follows: 5 for left main stem, 2.5 for proximal left anterior descending (LAD) or proximal circumflex (CX) artery, 1.5 for a the mid-segment of LAD, 1 for the distal segment of LAD, right coronary artery and mid/distal CX; and the multiplication factor 0.5 was assigned for other involved segments.
Patients with other conditions such as chronic and acute inflammatory diseases, stroke, heart failure disease, acute coronary syndrome, recent myocardial infarction (within the preceding 3 months), and also recent surgery operations (within the preceding 6 months) were not entered into the study. Similarly, the control group aside from not having the mentioned conditions also had no a previous clinical or diagnostic evidence of CAD.
Clinical and demographic information of the participants were also provided by clinical examination and medical records assessment. Individuals who had systolic/diastolic blood pressure >140/90 mmHg or being received antihypertensive drugs were defined as hypertensive. A fasting serum glucose ≥126 mg/dl or treatment with hypoglycemic medications was diagnosed as diabetes mellitus. Former or current use of any form of cigarette or tobacco was determined as smoking status. Family history of CAD was based on the evidence of CAD in first-degree relatives (at age <60 years). Individuals with hyperlipidemia were ascertained using one or more of the following parameters: serum total cholesterol ≥200 mg/dl, serum triglyceride >150 mg/dl, and  use of lipid-lowering agents. Written informed consents were signed by all individuals under the study. The study protocol was approved the University Ethics Committee.
Overnight fasting blood samples were drawn from all participants (before coronary angiography procedure). Serum samples, after isolation, were aliquoted and stored at −80°C until biochemical quantifications.
Serum biochemical measurements
Serum SFRP5 and oxidized low-density lipoprotein (Ox-LDL) concentrations were determined using commercial immunoassay kits (USCN Life Science Inc., Wuhan, China for SFRP5 and Mercodia, Uppsala, Sweden for Ox-LDL) according to their manufacturers' protocols. The intra- and inter-assay precisions of the assays were 8.3 and 10.7% for SFRP5 and 5.2% and 8.1% for Ox-LDL, respectively. Serum high-sensitivity C-reactive protein (hsCRP) concentration was assayed by immunoturbidimetry method on a Hitachi 902 autoanalyzer (Hitachi, Tokyo, Japan). Serum lipid profile (total cholesterol, triglycerides, HDL-cholesterol, and LDL-cholesterol) and glucose concentrations were also determined using automated enzymatic methods on the Hitachi 902 autoanalyzer.
All data were presented as mean ± standard deviation, median (25%–75% interquartile range), number and percent, as appropriate. Continuous variables between patient and control groups were compared by Mann–Whitney U-test or unpaired t-test. Categorical variables were compared using the χ2 test. Correlation of serum SFRP5 concentration with other clinical characteristics was explored using Pearson's correlations test. To evaluate the association between serum SFRP5 and CAD, a multivariate logistic regression analysis (after log-transforming the variables with skewed distribution), adjusting for other confounding covariates, was performed. We employ the receiver operating characteristic curve (ROC curve) analysis to clarify whether the serum SFRP5 could differentiate patients with CAD from controls. For all statistical analysis, the SPSS 22.0 software (SPSS Inc., Chicago, IL, USA) was applied and P < 0.05 was assumed as statistically significant.
| Results|| |
Clinical and demographic information of CAD patients and controls under the study are represented in [Table 1]. There were no significant differences between patients and controls regarding some clinical features such as age, gender, body mass index (BMI), hypertension, diabetes mellitus, hyperlipidemia, and smoking status. Lipid-lowering and cardiovascular medications were predominately consumed by CAD patients. Furthermore, patients demonstrated significantly higher concentrations of serum Ox-LDL and hs-CRP, as well as a higher prevalence of family history of CAD than the controls. On the contrary, CAD patients had considerably a lower serum SFRP5 in comparison to the controls [Figure 1].
|Table 1: Demographic and clinical characteristics of the coronary artery disease patients and controls under study|
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|Figure 1: Serum levels of Secreted frizzled-related protein 5 (SFRP5) in coronary artery disease (CAD) patients were significantly lower than in the control subjects (P<0.001). In the represented box plots, median and 25th-75th interquartile range (the edges and middle line of the boxes, respectively) of serum SFRP5 levels are exhibited|
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In bivariate correlation analyses, serum SFRP5 concentration was found to be significantly and inversely correlated with BMI, serum Ox-LDL, hsCRP, and LDL-cholesterol concentrations as well as the Gensini score in all participants [Table 2].
|Table 2: Correlations of secreted frizzled-related protein 5 with age, body mass index, Gensini score, and biochemical variables in all individuals under study|
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To signify the importance of serum SFRP5 as an independent predictor of CAD, a multiple logistic regression analysis, adjusting for the other potential confounding covariates under study, was performed [Table 3]. Among the covariates included in the analysis, serum SFRP5, Ox-LDL, and hs-CRP concentrations were emerged as independent predictors of CAD. Interestingly, we found serum SFRP5 concentration tended to be a stronger predictor of CAD as compared to Ox-LDL and hs-CRP in the multiple logistic regression analysis [Table 3].
|Table 3: Logistic regression analysis results for determining independent predictors of coronary artery disease|
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In another multiple logistic regression analysis, again adjusting for the potential confounding covariates, we sought to find the predictors of CAD severity, based on the angiographic Gensini scores. Low serum SFRP5 (0.65 (0.21–0.82, P = 0.036)) was appeared as a negative predictor of CAD severity while other covariates were shown not to be significant predictors of CAD severity.
Given the significant prediction power of serum SFRP5, Ox-LDL, and hs-CRP for CAD, we examined whether the serum concentration of these biomarkers would be of diagnostic value to differentiate CAD patients from controls. As shown in [Figure 2], ROC curve analysis revealed that from the biomarkers, serum SFRP5 could more strongly discriminate CAD patients from controls and therefore may also serve as a better diagnostic biomarker for CAD. According to the curve analyses, serum SFRP5 with the cutoff value 32.96 ng/mL, had a 75% sensitivity and 73% specificity which were notably higher than those for Ox-LDL (cutoff value 81.42 ng/mL; 70% sensitivity, and 67% specificity) and hsCRP (cutoff value 2.34 ng/mL; 68% sensitivity, and 59% specificity), respectively.
|Figure 2: Receiver operating characteristic (ROC) curve analyses of SFRP5, Ox-LDL and hsCRP. AUC is the area under the curve that along with its 95% confidence interval (95% CI) is depicted for the three biomarkers. SFRP5 with the higher AUC of 0·82 (95% CI 0·73–0·91; P = 0·01) was proved to be a stronger discriminating biomarker of CAD|
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| Discussion|| |
Results of the current study revealed that serum level of the anti-inflammatory adipokine, SFRP5, in contrast to the established inflammatory biomarkers hsCRP and ox-LDL, is significantly decreased in CAD patients as compared to controls. More importantly, these results provide evidence that serum SFRP5 is independently and inversely associated with the presence and severity of CAD.
The implication of SFRP5 as an anti-inflammatory biomarkers was recently demonstrated in a study in patients with CAD in comparison with non-CAD patients. In that recent study, the decreased level of SFRP5 in CAD patients and its inverse association with the presence and severity of CAD are consistent with the findings of the current study.
The mechanisms by which low SFRP5 levels are associated with increased risk of CAD are not unequivocal. One mechanistic relation of SFRP5 with CAD may be due to the suppression of inflammatory mediators that are produced by macrophages and/or adipocytes. Furthermore, a strong link between serum SFRP5 levels and oxidative stress was reported in human. SFRP5 has been shown to suppress inflammatory response in rheumatoid arthritis fibroblast-like synoviocytes. In low-grade inflammatory condition, such as obesity and type 2 diabetes decrease of SFRP5 is accompanied by a significant increase of the pro-inflammatory risk factor, Wnt5a.,,, It should be noted that Wnt signaling is implicated in atherosclerosis and cardiovascular disease. In addition, SFRP5 has been shown to repress inflammatory reaction following ischemia/reperfusion damage in the heart of mice through antagonizing the noncanonical Wnt5a signaling. Therefore, it can be speculated that in reduced SFRP5 conditions, the inflammatory mediators, oxidative stress and Wnt5a signaling are potentiated, providing an inflammatory state that leads to chronic inflammatory-related comorbidities such as CAD. Indeed, the inverse correlation of serum SFRP5 with hsCRP and Ox-LDL levels that we found in the present study is of particular relevance to the anti-inflammatory, as well as the anti-oxidative function of SFRP5 in CAD. A relatively same inverse correlation between serum SFRP5 and hsCRP levels was also hinted in the study on CAD and non-CAD patients by Miyoshi et al. hsCRP and Ox-LDL, respectively, have been considered as suitable surrogate biomarkers of low-grade inflammatory and oxidative state in cardiovascular diseases., The casual relationships between serum SFRP5 and hsCRP and/or Ox-LDL are not decisively known. Although the possible impacts of inflammatory mediators releasing from macrophages/adipocytes  and the oxidative stress phenomenon, all secondary to low SFRP5 status, on hsCRP production, and LDL oxidation cannot be excluded, other underlying causes need to be explored.
Of worthy to note in the present study, is the capability of serum SFRP5 that might serve as a potential diagnostic and prognostic biomarker for CAD. Here, regarding the discriminatory power of serum SFRP5 for CAD, as well as its relation with the severity of CAD, our results are relatively comparable with those attained in the aforementioned study by Miyoshi et al. However, since to date, only two studies have addressed the diagnostic and prognostic applicability of serum SFRP5 in CAD, additional studies with larger sample size would be mandatory to clarify the issue.
Apart from the limitations inherent to the cross-sectional designing and comparison and/or correlational analyzing of data in the present study, our findings are the second that corroborate the link between SFRP5 and CAD and shed light to its clinical significance. However, the exact role of SFRP5 in CAD and its fitness toward clinical setting await for further studies with larger number of individuals.
| Conclusions|| |
In summary, our results elucidated that serum SFRP5 is decreased in CAD patients as compared to controls. Moreover, the serum SFRP5 level was negatively and significantly correlated with the presence and severity of CAD and seems to be a potential biomarker of CAD.
The authors would like to appreciate all the patients for complying to participate in the study.
Financial support and sponsorship
This research was supported by Islamic Azad University under the grant number 132655.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Ouchi N, Higuchi A, Ohashi K, Oshima Y, Gokce N, Shibata R, et al.
Sfrp5 is an anti-inflammatory adipokine that modulates metabolic dysfunction in obesity. Science 2010;329:454-7.
Nakamura K, Fuster JJ, Walsh K. Adipokines: A link between obesity and cardiovascular disease. J Cardiol 2014;63:250-9.
Kim J, Kim J, Kim DW, Ha Y, Ihm MH, Kim H, et al.
Wnt5a induces endothelial inflammation via beta-catenin-independent signaling. J Immunol 2010;185:1274-82.
Christman MA 2nd
, Goetz DJ, Dickerson E, McCall KD, Lewis CJ, Benencia F, et al.
Wnt5a is expressed in murine and human atherosclerotic lesions. Am J Physiol Heart Circ Physiol 2008;294:H2864-70.
Miyoshi T, Doi M, Usui S, Iwamoto M, Kajiya M, Takeda K, et al.
Low serum level of secreted frizzled-related protein 5, an anti-inflammatory adipokine, is associated with coronary artery disease. Atherosclerosis 2014;233:454-9.
Hu Z, Deng H, Qu H. Plasma SFRP5 levels are decreased in Chinese subjects with obesity and type 2 diabetes and negatively correlated with parameters of insulin resistance. Diabetes Res Clin Pract 2013;99:391-5.
Hu W, Li L, Yang M, Luo X, Ran W, Liu D, et al.
Circulating sfrp5 is a signature of obesity-related metabolic disorders and is regulated by glucose and liraglutide in humans. J Clin Endocrinol Metab 2013;98:290-8.
Gensini GG. A more meaningful scoring system for determining the severity of coronary heart disease. Am J Cardiol 1983;51:606.
Carstensen M, Herder C, Kempf K, Erlund I, Martin S, Koenig W, et al.
Sfrp5 correlates with insulin resistance and oxidative stress. Eur J Clin Invest 2013;43:350-7.
Kwon YJ, Lee SW, Park YB, Lee SK, Park MC. Secreted frizzled-related protein 5 suppresses inflammatory response in rheumatoid arthritis fibroblast-like synoviocytes through down-regulation of c-Jun N-terminal kinase. Rheumatology (Oxford) 2014;53:1704-11.
Schulte DM, Müller N, Neumann K, Oberhäuser F, Faust M, Güdelhöfer H, et al.
Pro-inflammatory wnt5a and anti-inflammatory sFRP5 are differentially regulated by nutritional factors in obese human subjects. PLoS One 2012;7:e32437.
Bilkovski R, Schulte DM, Oberhauser F, Mauer J, Hampel B, Gutschow C, et al.
Adipose tissue macrophages inhibit adipogenesis of mesenchymal precursor cells via wnt-5a in humans. Int J Obes (Lond) 2011;35:1450-4.
Jaikanth C, Gurumurthy P, Indhumathi T, Cherian KM. Emergence of SFRP5 as a pleiotropic adipocytokine and its association with wnt signaling pathways. Minerva Endocrinol 2017;42:280-9.
Catalán V, Gómez-Ambrosi J, Rodríguez A, Pérez-Hernández AI, Gurbindo J, Ramírez B, et al.
Activation of noncanonical wnt signaling through WNT5A in visceral adipose tissue of obese subjects is related to inflammation. J Clin Endocrinol Metab 2014;99:E1407-17.
Marinou K, Christodoulides C, Antoniades C, Koutsilieris M. Wnt signaling in cardiovascular physiology. Trends Endocrinol Metab 2012;23:628-36.
Nakamura K, Sano S, Fuster JJ, Kikuchi R, Shimizu I, Ohshima K, et al.
Secreted frizzled-related protein 5 diminishes cardiac inflammation and protects the heart from ischemia/Reperfusion injury. J Biol Chem 2016;291:2566-75.
Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO 3rd
, Criqui M, et al.
Markers of inflammation and cardiovascular disease: Application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003;107:499-511.
Peluso I, Morabito G, Urban L, Ioannone F, Serafini M. Oxidative stress in atherosclerosis development: The central role of LDL and oxidative burst. Endocr Metab Immune Disord Drug Targets 2012;12:351-60.
Biotechnology and Medicinal Plants Research Center, Ilam University of Medical Sciences, Banganjab St., Ilam
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]