Association of plasma soluble E-selectin and adiponectin with carotid plaque in patients with systemic lupus erythematosus
Introduction
Systemic lupus erythematosus (SLE) is a disease state posing several challenges to the clinician, including heterogeneity of presentation, undulating course, and an extraordinary risk for premature cardiovascular disease [1], [2]. Over two decades ago it was noted that the majority of deaths in patients with longer disease duration were attributed to atherosclerosis [1]. Indeed, the rate of myocardial infarction in women aged 35–44 years is 50 times greater than expected [2]. Patients with SLE have an increased atherosclerotic risk despite adjustment for traditional Framingham risk factors [2], [3]. Risk factors among SLE patients are somewhat controversial but may include longer duration of disease and lower likelihood of treatment with prednisone, cyclophosphamide, or hydroxychloroquine [4]. Thus, inflammation related to underlying disease is likely to be contributory. McMahon et al. have recently shown that plasma from SLE patients with premature atherosclerosis is enriched in proinflammatory HDL [5]. However, the inflammation may be clinically subtle since detectable cardiovascular events have been unexpectedly reported in SLE patients with extended periods of quiescence [6] and subclinical atherosclerosis has not correlated with disease activity index scores [4]. Thus, identification of biomarkers associated with atherogenic injury which might be present, independent of recognized lupus activity, should advance understanding of the pathology and guide prophylaxis for at risk subgroups.
The endothelium merits focus since it provides the physiologic boundary which limits extravasation and diapedesis of inflammatory cells. The generation of nitric oxide by the endothelium also promotes relaxation of the contractile elements of the smooth muscle of the arterial blood vessels. In atherogenic disease, endothelial protection is subverted perhaps because of a loss of boundary function via detachment of endothelial cells into the circulation and/or a change in the endothelial cell phenotype. Increased levels of circulating endothelial cells (CECs) have been observed in patients with active disease [7] and apoptotic CECs have been reported in SLE patients with diminished flow mediated dilatation (FMD) [8]. Soluble E-selectin (sE-selectin), likely shed from an abnormally activated endothelium, has been recently associated with atherosclerosis as defined by an abnormal coronary artery calcium assessed using electron beam computed tomography EBCT [9]. An integral membrane protein expressed on endothelial cells, endothelial protein C receptor (EPCR) has both anti-inflammatory and anti-thrombotic properties via its role in generating activated protein C. A recent study has linked increased atherosclerotic risk to shedding of the EPCR from the endothelial cell surface [10].
While these studies have highlighted the potential association of markers directly reflecting injury, absent is a focus on protective (anti-injury) molecules such as the adipocyte-derived protein, adiponectin. Germane to the consideration of protection is the relationship of adiponectin to atherosclerosis. Adiponectin, when elevated in peripheral blood is reported to promote a wide range of benefit at the site of blood vessel injury, such as the downregulation of adhesion molecules by attenuating the nuclear factor kB pathway [11], [12]. Adiponectin accumulates in the sub-endothelium of injured human arteries where it inhibits monocyte adhesion to endothelial cells and ultimately inhibits the migration and proliferation of vascular smooth muscle, which contributes to the atherosclerotic process [13]. In addition, adiponectin was found in blood vessel walls after experimental endothelial injury [14], and was strongly expressed around infarcted but not normal myocardium [15], supporting a role in vascular and endothelial remodeling.
Accordingly, this study was initiated to explore the endothelial contribution to cardiovascular risk in SLE. This was approached by evaluation of carotid ultrasonography in 119 SLE patients and 71 age and sex matched controls. An assessment of the endothelial contribution was made by evaluating a panel of biomarkers chosen to reflect pro- and anti-atherogenic injury.
Section snippets
Study population
This study and its informed consent form were approved by the Institutional Review Board of the New York University School of Medicine. During the period from August 2005 to July 2007, 119 patients were enrolled from the Lupus Clinic at the NYU-Hospital for Joint Diseases and the private practices of NYU physicians. All patients fulfilled at least four of the revised American College of Rheumatology criteria for the diagnosis of SLE [16]. Seventy-one healthy employees of the NYU Langone Medical
Comparison of patients with SLE and controls
The demographics of the 119 patients with SLE and 71 healthy controls are shown in Table 1. The cohort was ethnically diverse, including a minority of Caucasian subjects (41%). Hypertension was more common in SLE patients (36% vs 12% of controls; p = 0.0006). HDL and total cholesterol were lower in patients (patients vs controls; 57.2 mg/dL vs 63.6 mg/dL, p = 0.03; 177 mg/dL vs 188 mg/dL, p = 0.039, respectively), consistent with findings from prior studies [4]. There were no differences in LDL, TG,
Discussion
Premature atherosclerosis is a consistent feature of SLE and herein extends across all ethnicities. Carotid plaque was observed in over twice the proportion of lupus patients compared to age-, sex- and race/ethnicity-matched controls. Excess prevalence of plaque was seen beginning in the 5th decade of life. On multivariate analysis, age, SLE disease duration, sE-selectin, and adiponectin were the only independent predictors of plaque. Among lupus patients with plaque, elevations in these
Funding
This work was supported by a research grant to R.M.C. from the Lupus Research Institute, New York, NY. and by NIH/NCRR M01 RR0096. P.M.I. was supported by SLE Foundation, Inc. H.C. was supported by the Arthritis Foundation, New York Chapter.
Acknowledgements
We thank Drs. ER Gehrie, H Comerci, and E. Karis who worked on this project during their residencies/fellowships.
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