| Background Coronary artery atherosclerotic disease(CAD), also known as ischemic heart disease(IHD), atherosclerotic heart disease, atherosclerotic cardiovascular disease, and coronary heart disease, is a group of diseases that includes: stable angina, unstable angina, myocardial infarction, and sudden coronary death. Several types of immune cells dominate the initiation of atherosclerotic lesions, and their effector chemokines and cytokines accelerate plaque development. Moreover, the activation of inflammation leads to further plaque destabilization and results in acute coronary syndrome(ACS). Regulatory T(Treg) cells are a novel subset of T cells that play an important role in the modulation of immune responses and the control of deleterious immune activations because of their immunoregulatory and immunosuppressive functions. Treg cells that constitutively express CD4, CD25, and forkhead winged helix transcription factor(Foxp3) have been demonstrated to play a significant role in the development of atherosclerosis. Several animal experiments have indicated that Treg cell levels were decreased in the atherosclerotic animal models and that an increase in Treg cell numbers and function was related to reduced atherosclerotic plaques. Therefore, it is speculated that Treg cell defects could aggravate the plaque development during human atherosclerosis. Several clinical studies that investigated circulating Treg cells, defined as CD4+CD25+ T cells, in patients with coronary heart disease have offered conflicting results in patients with ST elevation acute myocardial infarction(STEMI). The explanations for the inconsistency may be the difference in experimental methods and the quality of Treg cell confirmation. However, all published studies have reported reduced Treg cell numbers in patients with non-ST elevation acute coronary syndrome(NSTACS; including NSTEMI and unstable angina), revealing that the defects in Treg cells were responsible for the immune activation observed in the NSTACS patients. The mechanisms responsible for the peripheral Treg cell defects in the NSTACS patients remain mostly unclear. Low numbers of Treg cells were reported in human atherosclerotic plaques, suggesting that mechanisms other than Treg cell reallocation account for the peripheral Treg cell defects in the NSTACS patients. Recent studies have also demonstrated that the absence or low expression of CD127 can be used as a new and reliable marker of human Treg cells and correlates well with Foxp3.Soluble fibrinogen-like protein 2(s FGL2) is a novel effector mainly secreted by CD4+CD25+Foxp3+ Treg and tolerogenic CD8+CD45RClow Treg. It is one form of fibrinogen-like protein 2(FGL2), which belongs to fibrinogen-related proteins superfamily. The gene FGL2 was originally cloned from cytotoxic T lymphocyte(CTL), and the encoded protein shares a 36% homology with the fibrinogen A- and F- chains and a 40% homology with the fibrinogen-related domain(FRED) of tenascin. It is now well characterized two forms; the membrane bound FGL2(m FGL2) and the soluble FGL2. m FGL2, a 70 k Da molecule, exerts procoagulative activity and promotes thrombosis, generating thrombin directly and plays an important role in the innate immunity. s FGL2 which has a 50 k Da weight, totally different from m FGL2, presents an ability in immunoregulatory and contradictory properties in tissue injuries. As s FGL2 is a soluble protein, it can be easily detected from samples of serum, plasma, cell culture supernatant, and tissue homogenate using enzyme-linked immunosorbent assay or Western blotting. The purpose of this study was to investigate the relationship between circulating s FGL2 concentrations and severity of coronary artery disease in patients who underwent first-time angiography for suspected CAD.ObjectiveTo investigate the relationship between circulating s FGL2 concentrations and severity of coronary artery disease in patients who underwent first-time angiography for suspected CAD and their relationship with inflammation cytokinesMethods Serum soluble fibrinogen-like protein 2(s FGL2) concentrations were measured in 102 consecutive patients with ACS, stable angina pectoris(SAP), and 50 healthy persons by ELISA. Circulating CD4+CD25+CD127low Treg were determined by flow cytometry and their effecter cytokines including TGF-β1 and IL-10 were also evaluated by ELISA. Serum levels of inflammation factors including tumor necrosis factor alpha(TNF alpha) and hypersensitive C-reactive protein(hs-CRP) were determined by ELISA, too. RT-PCR was perfomed to determine FGL2 m RNA expression in peripheral blood lymphocyte.Results 1. There were no statistical significance between groups in clinical baseline including age, gender, smoking, blood pressure, FBG, Total cholesterol, Total cholesterol(TC), high-density lipoprotein cholesterol(High density lipoprotein, HDL), Triglycerdes(TG), and Creatinine(Cr)(P > 0.05). Low density lipoprotein(LDL) levels were higher in ACS group than that in the SAP and healthy persons(P < 0.05).2. The percentage of CD4+CD25+CD127low Treg was significantly decreased in ACS patients compared with SAP and healthy persons(F = 173.522, P < 0.01). Further analysis showed no significant change of percentage of Treg between SAP and healthy persons. Peripheral blood Treg ratio is lower in ACS group as compared with SAP group and healthy persons(P < 0.01).3. The serum level of s FGL2 was significantly decreased in ACS patients compared with SAP and healthy persons(F = 74.16, P < 0.01). Further analysis showed no significant change of s FGL2 between SAP and healthy persons. Serum s FGL2 is lower in ACS group as compared with SAP group and healthy persons(P < 0.01).4. The serum level of IL-10 and TGF-β1 were significantly decreased in ACS patients compared with SAP and healthy persons(P < 0.01) while TNF-α and hs-CRP were significantly higer in ACS patients than that in SAP patients and healthy persons. Further analysis showed no significant change of these four cytokines between SAP and healthy persons. However, significant changes of these cytokines were observed in ACS group as compared with SAP group and healthy persons(P < 0.01).5. The level of FGL2 m RNA was significantly decreased in ACS patients compared with SAP and healthy persons(P < 0.01). Further analysis showed no significant change between SAP and healthy persons. However, a significant change of FGL2 m RNA was observed in ACS group as compared with SAP group and healthy persons(P < 0.01).6. Bivariate correlation analysis showed that the serum level of s FGL2 was positively correlated with CD4+CD25+CD127lowTreg, serum IL-10 and TGF-β1 level while was negatively correlated with TNF-α and hs-CRP. Multivariate linear regression was performed to estimate the effects of serum s FGL2 level together with several other cardiovascular risk factors in the presence of CAD. The dependent variable was s FGL2. The regression equation included gender, age, body mass index, smoking, diabetes, fasting glucose, triglycerides, TC, LDL-C, HDL-C and Treg. As a result, Treg percentage and serum IL-10 level were associated with serum s FGL2 level. The regression equation was s FGL2=2.942×Treg + 0.327×IL-10 +1.828, r2=0.459.Conclusion Decreased concentration of s FGL2 is an independent risk factor for ACS. Change in s FGL2 concentration can reflect the levels of circulating CD4+CD25+CD127low Treg and IL-10. s FGL2 may participate in the occurrence and development of ACS. |
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