The role of oxidized low-density lipoprotein in breaking peripheral Th17/Treg balance in patients with acute coronary syndrome

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Abstract

Oxidized low-density lipoprotein (ox-LDL) is an instrumental factor in atherogenesis, however, the effects of ox-LDL on the balance of Th17/Treg in acute coronary syndrome [ACS, including unstable angina (UA) and acute myocardial infarction (AMI)] is still unclear. CD4+CD25+ regulatory T (Treg) cells and Th17 cells, subsets of T-helper cells, play important roles in peripheral immunity and their imbalance leads to the development of tissue inflammation and autoimmune diseases. However, few studies have explored the effect of Th17/Treg balance in plaque destabilization and the onset of ACS. To explore the shift of Th17/Treg balance in ACS patients and the effect of ox-LDL on the balance, we examined the frequencies of Th17 and Treg cells, key transcription factors and relevant cytokines in patients with AMI, UA, stable angina (SA) and controls. We analysed the correlations of serum ox-LDL to Th17/Treg frequency, and the effects of ox-LDL on Th17/Treg cells in vitro. Our study demonstrated that ACS patients have shown a significant increase of Th17 frequency, RORγt expression and serum Interleukin 17 (IL-17), and a obvious decline of Treg frequency, Foxp3 expression, suppressive function, and serum IL-10. Serum ox-LDL positively correlated with the frequency of Th17 cells and negatively correlated with the frequency of Treg cells. In vitro incubation of peripheral blood mononuclear cells from controls with ox-LDL resulted in a significant reduction of Treg cells and a significant elevation of Th17 cells in a dose- and time-dependant manner. Treg and Th17 cells from ACS patients were significantly more susceptible to ox-LDL-mediated alterations. Th17/Treg numerical and functional imbalance exists in ACS patients, and ox-LDL has a direct effect on Th17/Treg imbalance which may contribute to the occurrence of ACS.

Introduction

Atherosclerosis (AS) is a chronic inflammatory disease in which immune mechanisms appear to make great effect, and atherogenesis involves various immune cells, particularly T lymphocytes, such as CD4+ T-helper cells [1], [2]. Acute coronary syndrome (ACS) occurs as a consequence of coronary plaque erosion or rupture and T lymphocytes play an important role in these coronary events [3]. CD4+CD25+ regulatory T (Treg) cells and T-helper 17 (Th17) cells are 2 original subsets distinguished from Th1 and Th2 cells. Treg cells expressing the forkhead/winged helix transcription factor (Foxp3), a fraction of inflammatory-regulated negative cells, have important effects on the maintenance of immune tolerance and immune homeostasis by contact-dependent suppression or by the release of anti-inflammatory cytokines, such as interleukin (IL)-10 and transforming growth factor (TGF)-β[4]. Th17 cells expressing retinoic acid-related orphan receptor γt (RORγt) exert an important effect on the pathogenesis of many experimental autoimmune diseases and human inflammatory conditions by producing IL-17, tumor necrosis factor (TNF)-α and IL-6 [5]. The Th17/Treg imbalance could be critical in the development of tissue inflammation and autoimmune diseases [6]. However, Th17/Treg balance in AS, especially ACS patients has not been fully investigated.

Oxidized low-density lipoprotein (ox-LDL) is a key factor in the initiation and progression of atherosclerosis and contributes to endothelial dysfunction and plaque destabilization through multiple mechanisms [7], [8]. It is unclear whether ox-LDL also affects AS and ACS patients by disrupting the balance of the peripheral Tregs and Th17 cells.

In this study, we have examined the balance of Th17/Treg cells in ACS patients, and the effects of ox-LDL on these cells.

Section snippets

Patients

All patients gave written informed consent prior enrolment into the study. We examined patients at Anhui provincial hospital who underwent diagnostic catheterisation between July 2007 and June 2009. Patients were classified into 4 groups: acute myocardial infarction (AMI) patients, unstable angina (UA) patients, stable angina (SA) patients and control subjects with normal coronary arteries (NCA), Patients with ACS and SA had a similar extent of coronary atherosclerosis. There were no evident

Characteristics of patients

Table 1 shows the characteristics of patients. There were no significant differences in age, gender, CAD extent, hypertension, diabetes mellitus, smoking rate, obesity, high-density lipoprotein-cholesterol (HDL-C), and very low-density lipoprotein-cholesterol (VLDL-C) concentrations among patients with AMI, UA, and SA.

Decrease of Treg cells in ACS patients

The frequencies of Treg (CD4+CD25high/CD4+, CD4+CD25+CD127lo/CD4+, and CD4+CD25+Foxp3+/CD4+ T cells) cells were significantly lower in AMI and UA patients than in the SA and NCA

Discussion

Our study indicate that the shift of the Th17/Treg cell balance from Treg cells towards Th17 cells exists in ACS patients, and that this ox-LDL-mediated change is associated with the imbalance of Th17/Treg cells.

Treg cells may suppress proatherogenic immune responses partly by secretion of anti-inflammatory cytokines, such as IL-10. The normal function of Treg cells may be essential to maintain the homeostasis of different subsets of T cells in the vessel wall [12]. There are reduced numbers of

Acknowledgments

This work was supported by National Natural Science Foundation of China (No. 30971226) and Natural Science Foundation of Anhui province of China (No. 090413091).

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1

These authors contributed equally to this work.

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