The “atheroprotective” mediators apolipoproteinA-I and Foxp3 are over-abundant in unstable carotid plaques☆
Introduction
Inflammatory processes play an important role in several stages of atherosclerosis, including increasing the propensity of plaques to rupture [1], [2], [3]. Atherosclerotic plaques from symptomatic patients tend to exhibit significant infiltration by macrophages, T cells and pro-inflammatory cytokines and chemokines. These inflammatory cells release matrix-degrading enzymes and thrombogenic substances that may result in plaque disruption, local thrombosis and subsequent clinical events, such as acute coronary and cerebrovascular syndromes [4], [5]. Conversely, stable plaques are characterised by significantly fewer inflammatory cells [6].
Although the association between pro-inflammatory cells and mediators and unstable plaques has been well established, the local role of putative anti-inflammatory moieties has not been well characterised. Two key anti-inflammatory markers studied extensively to date include apolipoproteinA-I (apoA-I), the major protein constituent of High Density Lipoproteins (HDL) and T-regulatory (Treg) cells. Population studies have shown a consistent and significant negative correlation between plasma HDL and cardiovascular events [7]. Recently it has been shown in vitro and in vivo, that apoA-I alone or as a component of HDL, can reduce vascular inflammation [8], [9]. However its presence and role in human atherosclerotic plaque is much less well defined. Furthermore, it is well established that inflammatory T cells, characterised by the expression of CD3 antigen, are found in significantly greater numbers in unstable plaques compared with stable plaques, and play a pivotal role in local inflammation [1], [10]. On the other hand, a subset of T cells, Treg, has been shown in animal studies to have protective effects against immune-mediated vascular inflammation [11]. However, the role of Treg cells and their major transcriptional protein, Foxp3, has not been well defined in human atherosclerotic plaque.
Therefore, we aimed to study the amounts and distribution of apoA-I and Foxp3 in human carotid plaque, because of their increasing profile in the literature as potent anti-inflammatory mediators. Moreover, we aimed to correlate their presence with patient characteristics, chiefly stable versus unstable disease.
Section snippets
Patients
Fifty seven consecutively seen, consenting patients with haemodynamically significant carotid artery disease undergoing endartectomy, were evaluated. Indications for surgery were based on NASCET [12] and ACAS [13] criteria for symptomatic and asymptomatic subjects respectively. The carotid stenoses were diagnosed and classified by colour duplex ultrasound according to consensus criteria [14]. Patients were classified as symptomatic according to the presence or absence of cerebrovascular
Results
Baseline patient characteristics did not differ significantly between study groups (Table 1).
Significantly greater areas of fibrous tissue were found in plaques from asymptomatic subjects compared with symptomatic subjects (35.2 ± 10.7% asymptomatic, 17.1 ± 6.7% symptomatic, p < 0.05). Immunohistochemical analysis revealed significantly greater areas of positive staining for macrophages (CD68 positive cells) (2.7 ± 0.5% asymptomatic, 9.2 ± 1.5% symptomatic, p < 0.001), the inflammatory chemokine, MCP-1 (1.3
Discussion
Inflammation is involved in several key stages of plaque development, and especially so, in the process of plaque destabilisation, leading to symptoms of “unstable” cardiovascular disease [3], [15]. In the current study, our immunohistochemical analysis of human atherosclerotic lesions demonstrated the presence of two novel potentially anti-inflammatory moieties, apoA-I, the major protein constituent of HDL and Foxp3, the major transcription protein of Treg cells. Furthermore, significantly
Acknowledgement
The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [32].
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Dr Patel is supported by a postgraduate scholarship from the National Heart Foundation of Australia. Professor Celermajer is supported by Grant 222722 from the National Health and Medical Research Council of Australia.