Systemic Lupus Erythematosus: Atherosclerotic Risk and the Link to Cholesterol Transport

Allison B. Reiss, M.D., Head, Inflammation Section, Chronic Disease and Aging, Department of Medicine, Winthrop-University Hospital, 222 Station Plaza North, Suite 502, Mineola, N.Y. 11501, USA, Assistant Professor of Medicine, SUNY Stony Brook School of Medicine, Tele: 516-663-3455, Email:

Allison B. Reiss

Magnitude of the Problem

Premature atherosclerotic cardiovascular disease (ASCVD) in systemic lupus erythematosus (SLE, lupus) is a major public health concern. The incidence of cardiovascular events including angina and myocardial infarction (MI) is significantly increased in SLE patients and the mortality rate for MI in SLE patients is ten times greater than in age-matched controls [1]. Up to 30% of deaths in SLE patients are due to coronary artery disease [2]. Acute MI and cerebrovascular accidents are greater than 8 times more common and CHF is 11 times more common in young women with SLE than in non-SLE young women [3]. Although the reasons underlying the association between SLE and increased risk for ASCVD are not yet clear, the impact of atherosclerosis on length and quality of life for persons with SLE is increasingly apparent as therapeutic interventions have improved prognosis and long-term survival [4,5].


ASCVD Risk Factors in SLE


Traditional risk factors for atherosclerosis, such as hypertension, hyperlipidemia, smoking, diabetes mellitus, and older age, lack predictive value in SLE patients [6]. Known risk factors for ASCVD that occur with greater frequency in SLE patients than in the general population include corticosteroid-induced hypercholesterolemia and hypertension associated with renal disease. However, even in studies controlling for steroid therapy and renal disease, the association between SLE and accelerated atherosclerosis, especially in premenopausal women who are generally at low risk, is inordinately high [1,7,8]. Many lupus patients have normal or low total cholesterol levels and although vasculitis rather than lipid abnormalities accounts for some of the thrombotic events in lupus patients, a majority develop lesions histologically indistinguishable from ordinary atherosclerotic plaques [9]. There is a clear need to develop biomarkers to better identify SLE patients at risk for atherosclerosis.


The Immune System in SLE and Cholesterol Homeostasis

Active inflammation in the artery wall and dysregulated cholesterol metabolism interact in the pathogenesis of atherosclerosis. Accumulating evidence indicates that the systemic inflammatory load in lupus disrupts cholesterol dynamics, increasing vulnerability to cholesterol accumulation in cells of the artery wall, including macrophages and endothelium [10]. SLE plasma contains various components that are not present in significant levels in normal plasma that could, individually or acting together, affect expression of genes implicated in atherosclerosis. SLE patient plasma may contain elevated levels of interferon (IFN)-γ, tumor necrosis factors (TNF), interleukins (IL), homocysteine, and complement C1q mediated immune complexes [11-13]. Our laboratory is studying the impact of the inflammatory milieu on the expression of a group of cholesterol transport genes that includes the cholesterol 27-hydroxylase, ATP binding cassette transporter (ABCA) 1, and CD36. Cholesterol 27-hydroxylase and ABCA1 are anti-atherogenic reverse cholesterol transport proteins that facilitate cholesterol efflux from peripheral cells while CD36 is a pro-atherogenic class B scavenger receptor responsible for oxidized LDL uptake and degradation by macrophages. All three of these genes play an important role in the maintenance of intracellular cholesterol homeostasis [14]. Suppression of ABCA1 and 27-hydroxylase expression and/or enhancement of CD36 expression in monocytes/macrophages leads to excessive lipid accumulation and foam cell transformation.

We have recently published our finding that plasma isolated from persons with lupus exhibits atherogenic potency by markedly stimulating expression of CD36 message and protein in cultured human monocyte-derived THP-1 cells as compared to age- and sex-matched control plasma [15]. SLE patient plasma increased CD36 mRNA expression by 71 ± 8% (n = 3, p < 0.001) above 50% control plasma. Fifty percent SLE patient plasma increased CD36 mRNA expression to 290 ± 12 % of control (n = 3, p < 0.001), compared with only 118 ± 3.7% of control in the presence of 50% control plasma (n = 3, Not Significant, Holm-Sidak). Fifty percent lupus plasma upregulated CD36 protein expression by 482.3 ± 76.2% (n = 4, p < 0.05), whereas 50% control plasma increased the CD36 protein level by only 239.8 ± 61.9% (n = 4, p = 0.026).

In a separate study, we demonstrated that 27-hydroxylase expression in both THP-1 and primary human aortic endothelial cells (HAEC) is modulated by SLE plasma [16]. After a 3 hour exposure, SLE plasma decreased 27-hydroxylase message in THP-1 monocytes by 47% ± 8% (p < 0.008) and in HAEC by 51 ± 5.5% (n = 5, p < 0.001). Blocking the effects of IFN-γ with a specific anti-receptor antibody prior to incubation in SLE patient plasma prevented the SLE plasma from decreasing 27-hydroxylase message. This implies a pro-atherogenic role for the cytokine IFN-γ in SLE. Overall, plasma from 70% of patients reduced 27-hydroxylase mRNA. Plasma samples from individual subjects exhibited distinct effects on these genes. Thus, SLE plasma acts in an atheroma-promoting manner by both increasing expression of a receptor that facilitates influx and decreasing expression of a transport protein crucial for efflux of cellular cholesterol As a physiologic correlate of the effect of SLE plasma on cholesterol flux, we measured foam cell transformation of THP-1 macrophages and found that lupus plasma more than doubled transformation of cholesterol-loaded THP-1 macrophages into foam cells (74 ± 3% versus 35 ± 3% for control plasma, n = 3, p < 0.001).         


Future Directions

Our data suggest that immunological reactants contribute to atherosclerosis by compromising expression of cholesterol transport proteins. The specific reactant(s) remain to be identified and their relative contributions quantified. Therapies that increase 27-hydroxylase or decrease CD36 expression could provide a new approach to treating atherogenic dyslipidemia. This work sets the stage for identifying a cholesterol transport gene expression profile unique to a high ASCVD risk subset of SLE patients and may extend beyond SLE to have predictive value in persons diagnosed with other autoimmune disorders or to the general population.


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