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Association of Soluble Fibrinogen-Like Protein 2 with the Severity of Coronary Artery Disease

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Association of Soluble Fibrinogen-Like Protein 2 with the Severity of Coronary Artery Disease □ ORIGINAL ARTICLE □ Association of Soluble Fibrinogen-like Protein 2 with the Severity of Coronary Artery Disease Jing Cheng 1, Yingying Chen 2, Banglong Xu 2, Jixiong Wu 2 and Fei He 2 Abstract Objective The purpose of this study was to investigate the relationship between circulating soluble fibrinogen-like protein 2 (sFGL2) concentrations and the severity of coronary artery disease (CAD) in pa- tients who underwent first-time angiography for suspected CAD. Methods Serum sFGL2 concentrations were measured in 102 consecutive patients by an enzyme-linked im- munosorbent assay (ELISA). The number of circulating CD4+CD25+CD127low T regulatory cells (Tregs) was determined by flow cytometry and effecter cytokines, including transforming growth factor-β1and interleukin-10 (IL-10), were also evaluated by an ELISA. Associations between sFGL2 and Tregs with angi- ographic indexes of the severity of CAD (i.e., number of diseased vessels and the modified Gensini score) were estimated. Results The sFGL2 levels in patients with angiographically confirmed CAD were significantly lower than those in patients with normal coronary arteries (26.95±8.53 vs. 9.88±5.46 ng/mL, p<0.001). Significant corre- lations were observed between the serum sFGL2 level and number of diseased vessels (r=-0.860, p<0.001) and modified Gensini score (r=-0.833, p<0.001). Using a multivariate analysis, the serum sFGL2 level was independently associated with the presence and severity of CAD. Conclusion The serum sFGL2 levels are significantly lower in the presence of CAD and correlate with the severity of the disease. Further clinical studies are needed to confirm the use of sFGL2 as a biomarker for the detection and extent of CAD. Key words: coronary artery disease, Gensini score, T regulatory cell, soluble fibrinogen-like protein 2 (Intern Med 55: 2343-2350, 2016) (DOI: 10.2169/internalmedicine.55.6149) teins super family and has been demonstrated to be a novel Introduction effector mainly secreted by CD4+CD25+ Tregs (5). The FGL2 gene was originally cloned from cytotoxic T lympho- Inflammation is implicated in the development and rup- cyte (CTL), and the encoded protein shares 36% homology ture of atheromatous plaques, and there is considerable evi- with the fibrinogen β-andγ-chains and 40% homology with dence supporting the involvement of CD4+CD25+ T regula- the fibrinogen-related domain (FRED) of tenascin (6-8). To tory cells (Tregs) in this process (1, 2). A previous study date, two forms of the FGL2 protein have been character- demonstrated that naturally occurring CD4+CD25+ Treg ized, the membrane bound FGL2 (mFGL2) and the soluble numbers were reduced and functional properties were com- FGL2. The former form is a 70 kDa molecule that exerts a promised in patients with acute coronary syndrome procoagulative activity (9) and promotes thrombosis (10), (ACS) (2). Animal experiments have also confirmed that generating thrombin directly and playing an important role upregulated CD4+CD25+ Tregs can attenuate both early and in innate immunity (6). sFGL2, which has a 50 kDa weight, advanced atherosclerotic lesions (3, 4). Soluble fibrinogen- exhibits immunoregulatory and contradictory properties dur- like protein 2 (sFGL2) belongs to the fibrinogen-related pro- ing tissue injury (11). A recent study has confirmed that １School of Nursing, Anhui University of Traditional Chinese Medicine, China and ２Department of Cardiology, Second Affiliated Hospital of An- hui Medical University, China Received for publication July 10, 2015; Accepted for publication November 19, 2015 Correspondence to Dr. Fei He, [email protected] 2343 Intern Med 55: 2343-2350, 2016 DOI: 10.2169/internalmedicine.55.6149 sFGL2 is an important molecule of Tregs in its function and and PE labelled anti-CD127 (BD Biosciences-Pharmingen). development (12), similar to transforming growth factor beta Briefly, 5×105 fresh PBMCs were incubated with specific (TGF-β) and interleukin-10 (IL-10) (13). The administration antibodies conjugated with fluorochrome (0.42 μg/mL of of a neutralizing antibody of sFGL2 inhibited the Treg activ- CD25-APC, 0.33 μg/mL of CD4-FITC and 0.33 μg/mL of ity in vitro (14-16). Hence, sFGL2 might play a more criti- CD127-PE) for 30 minutes at 4°C. The cells were then cal role in the Treg function. Previous studies have demon- washed using phosphate-buffered saline (PBS), resuspended strated the role of TGF-β and IL-10 in atherosclerosis and in Pharmingen Stain Buffer (PSB) and analyzed using a coronary artery disease (CAD) (17-19). In the present study, flow cytometer (FACSCalibur, BD Biosciences, San Diego, therefore, we aimed to investigate the association between USA). serum sFGL2 levels and the severity of CAD as assessed by Serum levels of sFGL2 validated angiographic indexes. The serum sFGL2 concentrations were determined using a Materials and Methods commercially available enzyme-linked immunosorbent assay (ELISA) kit (Bio Legend, San Diego, USA) according to the manufacturer’s instructions. Briefly, serum samples (30 Participants μL) were added to each well of a plate precoated with anti- The study population consisted of 102 consenting patients human FGL2 antibodies. Following 2-hour incubation at who underwent first-time coronary angiography for sus- room temperature and four washes with buffer, 100 μL of pected CAD from November 2012 to February 2014 at No. human FGL2 detection antibody were added to each well 2 Hospital of Anhui Medical University. Patients with histo- for 1-hour incubation at room temperature. The plate was ries of malignant disease, recent myocardial infarctions, un- washed again and treated with secondary horseradish stable angina, major trauma or surgery, renal insufficiency, peroxidase-conjugated antibodies. After another five washes, acute or chronic infectious disease, any kind of immune- 100 μL of substrate solution were then added for a 20- mediated disease, or recent prescription of statins were ex- minute incubation in the dark. After the reaction was cluded from the study. The diagnosis of CAD was con- stopped, the absorbance was measured at 450 nm using an firmed by coronary angiography using a quantitative coro- ELISA plate reader. The concentration was determined using nary angiographic system. CAD was defined as significant a standard curve according to the kit’s instructions. coronary stenosis with at least one main coronary vessel Measurement of inflammatory cytokines with !50% luminal narrowing. Non-CAD patients were de- fined as those with no stenosis or <50% diameter narrowing The levels of cytokines including TGF-β1, IL-10, high according to the quantitative coronary analysis (QCA) meas- sensitivity C-reactive protein (hs-CRP) and IL-10 were ana- urement. The study protocol was approved by our ethics lyzed using an ELISA, according to the manufacturer’s pro- committee, and all patients provided their informed consent. tocol (Invitrogen, Rochester, NY, USA). Prior to analyzing the TGF-β1 levels, 100 μL of serum were activated by add- Blood samples preparation ing 4 μL of 1 N HCl and incubated at room temperature for Peripheral blood samples were taken from an antecubital 15 minutes and neutralized using 3 μL 1 N NaOH. The acti- vein after overnight fasting and before angiographic proce- vated serum was then diluted 4× with assay buffer and dis- dures. Blood samples for sFGL2 determination were drawn, pensed into 96-well plates which were pre-coated with TGF- centrifuged, and stored at -80°C for subsequent assays. Be- β1 antibody, which was followed by the addition of the de- fore coronary angiography, complete blood counts and se- tection antibody and streptavidin-horseradish peroxidase rum creatinine and serum lipid profiles were determined in (HRP) conjugate. Specific binding was visualized after add- all patients. All patients had normal serum creatinine levels ing the substrate solution. A standard curve (log-log curve and normal white blood cell counts. Total cholesterol, tri- fit) was generated using respective recombinant human cy- glycerides, and high-density lipoprotein cholesterol were tokine and the absolute concentration of the cytokine in the measured using enzymatic methods after overnight fasting. serum was determined from this curve. The detection of IL- The low-density lipoprotein cholesterol concentration was 10, hs-CRP and IL-10 levels were performed as described calculated using the Friedewald formula. above without the serum activation procedure. Determination of circulating CD4+CD25+CD127low Coronary angiograms and quantitative analysis Tregs Coronary angiograms were obtained according to standard Peripheral blood mononuclear cells (PBMCs) were iso- techniques, and the severity of stenosis was assessed us- lated from the peripheral blood using a Ficoll gradient as ing quantitative coronary angiography as previously de- described previously (20). The presence of Tregs was deter- scribed (21). The angiograms and quantitative coronary an- mined by measuring the following markers: PC5-labelled giographic analysis were evaluated by 2 experienced inter- anti-CD4 (BD Biosciences-Pharmingen, San Diego, USA), ventional cardiologists blinded to the clinical information FITC-labelled anti-CD25 (eBioscience, San Diego, USA) and were scored according to 2 scoring systems: (1) the 2344 Intern Med 55: 2343-2350, 2016 DOI: 10.2169/internalmedicine.55.6149 Table 1. Clinical and Angiographic Characteristics of Patients with and without CAD. Variables Total Non-CAD (n=50) CAD (n=52) t/x2 p Men/Women 51/51 27/23 24/28
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