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Diagnostic Value of Circulating Progranulin and Its Receptor Epha2 in Predicting the Atheroma Burden in Patients with Coronary Artery Disease

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Diagnostic Value of Circulating Progranulin and Its Receptor Epha2 in Predicting the Atheroma Burden in Patients with Coronary Artery Disease Hindawi Disease Markers Volume 2021, Article ID 6653501, 9 pages https://doi.org/10.1155/2021/6653501 Research Article Diagnostic Value of Circulating Progranulin and Its Receptor EphA2 in Predicting the Atheroma Burden in Patients with Coronary Artery Disease Dan Tian,1 Qing Qin,2 Ruiyan Liu,2 Zi Wang,1 Xiaoyu Li,1 Qing Xu,1 and Qianzhou Lv 1 1Department of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China 2Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Disease, Shanghai, China Correspondence should be addressed to Qianzhou Lv; [email protected] Received 28 December 2020; Revised 27 March 2021; Accepted 12 April 2021; Published 22 April 2021 Academic Editor: Anna Birková Copyright © 2021 Dan Tian et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Progranulin (PGRN) and its potential receptor Eph-receptor tyrosine kinase-type A2 (EphA2) are inflammation- related molecules that present on the atherosclerotic plaques. However, the roles of circulating PGRN and EphA2 in coronary artery disease (CAD) remain unclear. Objective. To study the clinical significance of circulating PGRN and EphA2 levels in Chinese patients undergoing coronary angiography. Methods. Levels of circulating EphA2 fragments and PGRN were examined in 201 consecutive individuals who underwent coronary angiography for suspected CAD in our center from Jan 2020 to Oct 2020. Demographic characteristics, results of biochemical and auxiliary examinations, and other relevant information were collected. The coronary atheroma burden was quantified by the Gensini score and the existence of chronic total occlusion (CTO). Univariate analysis and multivariate logistic regression analysis were used to analyze the risk factors for acute coronary syndrome (ACS). In patients with ACS and SAP, a receiver operating characteristic (ROC) curve was generated to detect the accuracy and discriminative ability of levels of EphA2 and PGRN, the Gensini score, and cardiac injury biomarkers as surrogate endpoints for CTO. Results. Circulating EphA2 levels were significantly higher in patients with ACS than in subjects with stable angina pectoris (SAP) or control subjects (p <0:001). A positive linear correlation was verified between EphA2 levels and the Gensini score (r =0:306, p <0:001), and negative correlation was detected with the left ventricular ejection fraction (LVEF) (r = −0:405, p <0:001). Both PGRN and EphA2 were positively associated with cardiac injury biomarkers (i.e., NT-proBNP, cTnT, and hs-CRP) (p <0:05). The area under the ROC curve of PGRN and EphA2 was 0.604 and 0.686, respectively (p <0:01). Conclusions. Higher circulating EphA2 and PGRN levels were detected in patients with ACS than in patients with SAP. Circulating EphA2 and PGRN levels might be diagnostic factors for predicting the atheroma burden in patients with CAD. 1. Introduction nonculprit lesion-related major adverse cardiovascular events (MACEs) in patients with ACS after a successful cul- Coronary artery disease (CAD) remains the leading global prit lesion intervention [2]. Thus, early prediction of the ath- cause of morbidity and mortality. Acute coronary syndrome eroma burden in patients with CAD plays an essential role in (ACS) is an acute and dangerous type of CAD and the pri- determining the patient prognosis. Several cardiac injury bio- mary manifestation of atherosclerotic progression in the cor- markers are promising markers for atheroma burden and onary artery, which is closely related to endothelial have been reported to predict MACEs, such as N-terminal dysfunction, inflammation, and coagulation [1]. Rupture of pro B-type natriuretic peptide (NT-proBNP), cardiac tropo- atherosclerotic plaque and persistent thrombotic vessel nin (cTn), and high-sensitivity C-reactive protein (hs-CRP) occlusion at the site of plaque rupture have dominated our [3, 4]. thinking on ACS pathophysiology. Shan et al. found that an Progranulin (PGRN) is a secreted glycoprotein encoded increased baseline atheroma burden independently predicts by the GRN gene that is implicated in multiple pathological 2 Disease Markers Table 1: Baseline characteristics and biochemical index of the study participants. Variables Control (n =42) SAP (n =75) ACS (n =84) p value Males, n (%) 30 (71.4) 54 (72.0) 69 (82.1) 0.094 Age (y) (mean ± SD) 62:3±10:365:7±9:166:2±10:3 0.105 BMI (kg/m2) 24:6±3:325:2±2:624:5±3:3 0.471 Cardiovascular risk factor Hypertension, n (%) 24 (57.1) 49 (65.3) 51 (60.7) 0.663 Diabetes mellitus, n (%) 10 (23.8) 28 (37.3) 35 (41.7) 0.141 Smoking, n (%) 14 (33.3) 34 (45.3) 34 (40.5) 0.447 Biochemical index eGFR (mL/min/1.73 m2) 90.0 (82.0, 95.0) 85.0 (70.0, 90.0) 83.0 (71.5,96.0) 0.041 Total cholesterol (mg/dL) 131.8 (109.0, 164.9) 118.3 (103.6, 151.9)b 152.7 (133.4, 185.6)a <0.001 LDL (mg/dL) 56.1 (44.9, 87.4)b 48.9 (36.7, 75.8)b 85.4 (66.1, 116.4)a <0.001 Hemoglobin A1c (%) 5.8 (5.5, 6.1)b 6.2 (5.7, 7.1) 6.4 (5.6, 7.9)a 0.023 NT-proBNP (pg/mL) 51.7 (32.9, 128.5)b 89.6 (44.9, 195.8)b 497.0 (137.8, 1050.0)a <0.001 cTnT (ng/mL) 0.007 (0.005, 0.010)b 0.009 (0.006, 0.014)b 0.19 (0.04, 0.95)a <0.001 CK-MB (U/L) 15.0 (13.0, 17.0)b 14.0 (12.0, 17.0)b 21.0 (14.5, 56.0)a <0.001 hs-CRP (mg/L) 0.6 (0.3, 0.9)b 0.7 (0.4, 1.4)b 4.7 (1.0, 10.6)a <0.001 PGRN (ng/mL) 41.2 (31.0, 50.1) 39.7 (31.4, 46.7)b 43.3 (37.5, 53.1)a 0.036 EphA2 (pg/mL) 39.0 (23.8, 109.6)b 38.8 (21.3, 173.9)b 284.5 (199.4, 437.6)a <0.001 Gensini score 5.0 (1.5, 8.0)c 25.7 (16.5, 43.0)b 57.0 (38.0, 97.0)a <0.001 LVEF (%) 66.0 (64.0, 67.0)b 64.5 (61.0, 67.0)b 58.0 (48.0, 62.0)a <0.001 CTO 0 (0.0) 7 (9.5) 39 (46.4) <0.001 Data are expressed as mean ± standard deviation or median (interquartile range) or n (%). a,b,cSame letters indicate no statistical significance between groups based on Tukey’s HSD post hoc test. ACS: acute coronary syndrome; SAP: stable angina pectoris; BMI: body mass index; eGFR: estimated glomerular filtration rate; LDL: low-density lipoprotein; NT-proBNP: N-terminal pro B-type natriuretic peptide; cTnT: cardiac troponin T; CK-MB: creatine kinase- MB; hs-CRP: high-sensitivity C-reactive protein; PGRN: progranulin; EphA2: Eph-receptor tyrosine kinase-type A2; LVEF: left ventricular ejection fraction; CTO: chronic total occlusion. processes such as regulation of inflammation, promotion of ever, the clinical roles of PGRN and EphA2 in patients with proliferation, mediation of cell cycle progression, cell motil- CAD remain unclear. The study sought to identify the clini- ity, and neurotropic and lysosome regulation [5, 6]. Studies cal significance of EphA2 and PGRN in patients with CAD. have found that plasma PGRN levels are related to insulin resistance and inflammatory regulation [7, 8]. Kojima et al. 2. Materials and Methods first detected the expression of PGRN in atherosclerotic pla- ques [9]. In animal models, PGRN deficiency leads to severe 2.1. Study Population. The study recruited adult patients atherosclerotic lesions and increased age-related myocardial scheduled for coronary angiography at the Department of hypertrophy [10, 11]. Cardiology in Zhongshan Hospital Fudan University Eph-receptor tyrosine kinase-type A2 (EphA2) is also a between Jan 2020 and Oct 2020. Patients were included if promising cardiovascular molecule involved in the regulation they were between 40 and 85 y of age. The exclusion criteria of cell-cell interactions and angiogenesis [12]. According to were severe infectious diseases, severe liver or kidney insuffi- recent studies, EphA2(-/-)ApoE(-/-) mice show diminished ciency, and malignant diseases. All participants provided atherosclerotic plaque formation and reduced proinflamma- written informed consent, and the experimental scheme tory gene expression compared to ApoE(-/-) controls, which was approved by the Zhongshan Hospital Institutional Ethics identifies an unrecognizable role of EphA2 in regulating both Committee. The study was performed in accordance with the plaque inflammation and progression to advanced athero- Declaration of Helsinki. sclerotic lesions [12]. Additionally, EphA2 deficiency could exacerbate the myocardial injury and the progression of 2.2. Sample Collection and Measurement. Preangiography ischemic cardiomyopathy [13]. blood samples (4 mL) were obtained from the right jugular Interestingly, EphA2 is a functional receptor for PGRN vein of patients upon admission and rapidly centrifuged at that has been validated in vitro, and EphA2 silencing signifi- 3,000 rpm for 10 min at 4°C. Finally, approximately 2 mL of cantly prevents PGRN-mediated autoregulation [14, 15]. supernatants was transferred to RNase-free tubes and stored Moreover, PGRN degradation into granulin peptides might at a temperature of -80°C until subsequent assays. In all exacerbate inflammation in atherosclerotic values, which patients, the levels of EphA2 and PGRN were measured using contributes to the progression of atherosclerosis [16]. How- commercial high-sensitivity enzyme-linked immunosorbent Disease Markers 3 150 ns ⁎⁎⁎ 2500 ⁎⁎⁎ ⁎ 2000 100 1500 PGRN (ng/mL) 1000 50 (pg/mL) EphA2 500 0 0 Control SAP ACS Control SAP ACS (a) (b) ⁎⁎⁎ ⁎⁎⁎ 200 ⁎⁎⁎ 100 ⁎⁎⁎ 80 150 ⁎⁎⁎ 60 100 LVEF (%) LVEF 40 Gensini score 50 20 0 0 Control SAP ACS Control SAP ACS (c) (d) Figure 1: Difference of serum PGRN (a) and EphA2 (b) levels and Gensini score (c) and LVEF (d) between patients with the acute coronary syndrome (ACS) and (SAP) and control subjects.
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