Elsevier

Atherosclerosis

Volume 225, Issue 1, November 2012, Pages 224-230
Atherosclerosis

Complement system and small HDL particles are associated with subclinical atherosclerosis in SLE patients

https://doi.org/10.1016/j.atherosclerosis.2012.08.029Get rights and content

Abstract

Background

The complement system is involved in the pathogenic course of SLE. These patients exhibit metabolic disturbances in lipoprotein metabolism characterized by a pro-inflammatory status and an accelerated atherosclerosis.

The aim of this study is to investigate whether levels of the complement are associated to the presence of subclinical atherosclerosis, lipid and glucose metabolism and inflammatory markers in SLE patients.

Methods

Sixty-nine consecutive patients with SLE were recruited for the study. Fasting venous blood samples were collected on the same day as the measurements of cIMT were performed. Total plasma lipids and the distribution of subclasses of lipoproteins were analyzed by nuclear magnetic resonance spectroscopy.

Results

We found direct correlations between cIMT values and the levels of C3, C4 and CH50. In multivariate analyses, the mean cIMT from the three territories were predicted by age (β = 0.005, 95% CI: 0.002–0.007, P < 0.001) and the functional hemolytic assay of the complement activity CH50 (β = 0.003, 95% CI: 0.001–0.006, P < 0.0013). The complement components were associated with BMI, SBP and levels of glucose. Small, dense HDL particles also correlated with the three complement components C3, C4 and CH50 in bivariate analyses. In multivariate analyses small HDL particles predicted levels of C3: β = 0.024, 95% CI: 0.013–0.035, P < 0.001; and C4: β = 0.005, 95% CI: 0.002–0.008, P = 0.006.

Conclusions

Activation of the complement system measured by functional assay CH50 is related to subclinical atherosclerosis in quiescent lupus patients and is activated by the small dense HDL particles.

Highlights

► Complement system is associated with subclinical atherosclerosis in SLE patients. ► Small HDL particles predict levels of the complement components C3 and C4. ► Small HDL particles are pro-atherogenic in this population.

Introduction

Systemic Lupus Erythematosus (SLE) represents a chronic autoimmune inflammatory disease with an increased cardiovascular mortality and morbidity [1], [2]. The estimated prevalence of cardiovascular disease in this population lies between 6 and 10%, with an annual incidence of 1.3–1.5% [3], [4], [5].

This accelerated atherosclerosis observed in SLE patients cannot be entirely explained by classic cardiovascular risk (CVR) factors as hypertension, diabetes, smoking, obesity or dyslipidemia but also by some disease-related factors such as the duration of the disease, corticoid therapy and some inflammatory mechanisms. It has been proposed as ethiopatogenic factors of atherosclerosis in SLE patients elevated levels of CRP, anti-beta2GPI, anti-oxidized low-density lipoprotein and antiphospholipid antibodies, heat shock proteins, the nuclear protein high mobility group box 1 (HMGB1), or complement activation [6], [7], [8], [9], [10].

It is well recognized that the complement system plays an important role in the clinical course of SLE disease. It is known that hereditary complement deficiencies have been associated with an increased risk for SLE indicating a protective role of complement system in autoimmune disease as promotes the clearance of immune complexes and apoptotic cells from circulation. By the other hand, it has been recognized that there is an uncontrolled complement activation in SLE patients that is associated with disease-related complications and flares. This hypocomplementemia can be related to an excess of complement activation and consumption [11], [12].

It is recognized that the pathogenic process of atherosclerosis resembles a chronic inflammatory reaction involving components of both innate and adaptive immunity [13]. The existence of T-cells within plaque lesions or the presence of auto-antibodies against the endothelium has been observed in the general population [6].

Several proteins of the complement system, activation products, receptors and regulatory proteins [14], [15] have been detected in atherosclerotic lesions, and the deposition of C5b-9 has been shown to correlate with the disease state [16]. Modified lipoproteins and apoptotic/necrotic cells have been shown to activate both the alternative and the classical complement pathway by binding immunoglobulins and CRP in vitro [17], and signs of complement activation via these pathways have been detected in atherosclerotic lesions in vivo [18]. Furthermore, plasma levels of complement component 3 (C3) have been related to coronary artery disease measured by coronary angiography and to clinical ischemic events [19], [20]. These data suggest the relevance of the complement system in atherogenesis [21], [22].

Lipid and glucose metabolism is also related to the complement system. Several studies have shown that levels of C3 and C4 were associated with higher levels of triglycerides, low levels of HDL and insulin resistance, which are the metabolic syndrome compounds [22], [23], [24], [25]. This characteristic pro-atherogenic dyslipidaemia found in the metabolic syndrome is also characteristic of SLE patients [26], [27].

Furthermore, a fragment of C3 (C3a-des-Arg) is common to the fraction of the acylation-stimulating protein (ASP), which is the most potent agent to stimulate triglyceride synthesis and glucose membrane transport in human adipocytes. This might help to explain the association between complement, lipid metabolism, insulin resistance and postpandrial lipemia [28], [29], [30], [31].

Recently, new proteomic technologies applied to HDL composition have revealed that HDL plays a previously unsuspected role in regulating the complement system. The complement components C3, C4 and C9, and complement-regulatory proteins like vitronectin and clusterin have been found bound to HDL. These studies also showed that HDL from patients with CAD was enriched in C3 and C4 [32], [33]. These studies also add evidence that distinct HDL subpopulations contain distinct apolipoproteins, conferring different anti-inflammatory and antiatherogenic properties.

In summary, the complement system is involved in the pathogenic course of SLE and these patients exhibit metabolic disturbances in lipoprotein metabolism characterized by a pro-inflammatory status and accelerated atherosclerosis.

The aim of this study was to investigate whether levels of complement that plays a singularity in SLE was associated, as well, to the presence of subclinical atherosclerosis, lipid and glucose metabolism and inflammatory markers in SLE patients.

Section snippets

Study population

Sixty-nine consecutive patients with SLE were recruited from the outpatient clinic of autoimmune diseases from the Hospital Universitari de Sant Joan de Reus. Patients fulfilled at least four of the classification criteria of the American College of Rheumatology, as revised in 1997 [34]. None of them had an active disease, defined by an SLE disease activity index (SLEDAI) >4 nor chronic organ damage using the SLICC/ACR Damage Index (SDI).

Neither diabetes mellitus nor impaired renal function was

General characteristics of the study population

General clinic characteristics of the patients are described in Table 1. Briefly, the mean age of the patients recruited in the study was 48.89 (16.53) years. The median of duration of disease was 12.44 (10.05) years. As determined by routine biochemical analyses, the levels of glucose, lipid profile or hsCRP were within a normal range. Although the mean cardiovascular risk estimation was in the low range when calculated by Framingham risk score or SCORE, the mean of the cIMT value was

Discussion

In patients with an established SLE regular measurement of complement activity is a helpful guide for detecting a flare-up of the disease [11]. The complement system has also been related to the pathogenic process of atherosclerosis in the general population. Several complement protein depositions have been found in atherosclerotic lesions and have been associated with some cardiovascular risk factors like insulin resistance and lipid metabolism [15], [16], [17], [18], [19], [20]. In SLE

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